U.S. patent application number 13/249738 was filed with the patent office on 2012-02-16 for proteasome inhibitors and methods of using the same.
This patent application is currently assigned to CEPHALON, INC.. Invention is credited to Raffaella Bernardini, Alberto Bernareggi, Paolo G. Cassara, Sankar Chatterjee, Germano D'Arasmo, Sergio De Munari, Edmondo Ferretti, Mohamed Iqbal, Ernesto Menta, Patricia A. Messina McLaughlin, Ambrogio Oliva.
Application Number | 20120041196 13/249738 |
Document ID | / |
Family ID | 34278521 |
Filed Date | 2012-02-16 |
United States Patent
Application |
20120041196 |
Kind Code |
A1 |
Bernardini; Raffaella ; et
al. |
February 16, 2012 |
Proteasome Inhibitors and Methods of Using the Same
Abstract
The present invention provides boronic acid compounds, boronic
esters, and compositions thereof that can modulate apoptosis such
as by inhibition of proteasome activity. The compounds and
compositions can be used in methods of inducing apoptosis and
treating diseases such as cancer and other disorders associated
directly of indirectly with proteasome activity.
Inventors: |
Bernardini; Raffaella;
(Calci, IT) ; Bernareggi; Alberto; (Concorezzo
(MI), IT) ; Cassara; Paolo G.; (Monza (Milano),
IT) ; Chatterjee; Sankar; (Wynnewood, PA) ;
D'Arasmo; Germano; (Novate Milanese, IT) ; De Munari;
Sergio; (Milano, IT) ; Ferretti; Edmondo;
(Ravenna, IT) ; Iqbal; Mohamed; (Malvern, PA)
; Menta; Ernesto; (Cernusco sul Naviglio, IT) ;
Messina McLaughlin; Patricia A.; (Glen Mills, PA) ;
Oliva; Ambrogio; (Saronno (VA), IT) |
Assignee: |
CEPHALON, INC.
Frazer
PA
|
Family ID: |
34278521 |
Appl. No.: |
13/249738 |
Filed: |
September 30, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13020425 |
Feb 3, 2011 |
8058262 |
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13249738 |
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12496359 |
Jul 1, 2009 |
7915236 |
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13020425 |
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10918664 |
Aug 12, 2004 |
7576206 |
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12496359 |
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60495764 |
Aug 14, 2003 |
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Current U.S.
Class: |
544/229 ;
548/110; 560/115; 560/13; 560/28; 564/8 |
Current CPC
Class: |
A61P 37/06 20180101;
A61K 31/69 20130101; A61K 45/06 20130101; A61P 17/06 20180101; A61P
21/04 20180101; A61P 9/10 20180101; A61P 25/00 20180101; A61P 3/12
20180101; A61P 19/02 20180101; A61P 37/00 20180101; A61P 31/04
20180101; A61P 43/00 20180101; A61P 19/10 20180101; A61P 35/00
20180101; A61P 31/18 20180101; A61P 1/04 20180101; A61P 35/02
20180101; A61P 31/00 20180101; A61P 17/02 20180101; C07F 5/025
20130101; A61P 11/06 20180101 |
Class at
Publication: |
544/229 ; 564/8;
560/115; 560/13; 560/28; 548/110 |
International
Class: |
C07F 5/02 20060101
C07F005/02 |
Claims
1. A compound having Formula (I): ##STR00681## or a
pharmaceutically acceptable salt, stereoisomeric or tautomeric form
thereof, wherein: R.sup.1 is C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, or C.sub.3-C.sub.7 cycloalkyl;
R.sup.2 is H; Q is --B(OH).sub.2, --B(OR.sup.14).sub.2, or a cyclic
boronic ester wherein said cyclic boronic ester contains from 2 to
20 carbon atoms, and, optionally, a heteroatom which can be N, S,
or O; R.sup.14 is H, C.sub.1-C.sub.4 alkyl, cycloalkyl,
cycloalkylalkyl, aryl, or aralkyl; X is R.sup.AC(.dbd.O)--,
R.sup.ANHC(.dbd.O)--, R.sup.AS(.dbd.O).sub.2--, R.sup.AC(.dbd.O)--,
R.sup.ASC(.dbd.O)--, or R.sup.A; R.sup.A is C.sub.1-C.sub.20 alkyl
optionally substituted with R.sup.20; C.sub.2-C.sub.20 alkenyl
optionally substituted with R.sup.20; C.sub.2-C.sub.20 alkynyl
optionally substituted with R.sup.20; carbocyclyl optionally
substituted with 1-5 R.sup.22; or heterocarbocyclyl optionally
substituted with 1-5 R.sup.22; R.sup.20 is selected from the group
consisting of: --OR.sup.20a, --SR.sup.20a, --S(.dbd.O)R.sup.20a,
--S(.dbd.O).sub.2R.sup.20a, --S(.dbd.O).sub.2--NHR.sup.20a,
--SC(.dbd.O)R.sup.20a, --C(.dbd.O)R.sup.20a,
--C(.dbd.O)NHR.sup.20a, --C(.dbd.O)O--R.sup.20a, phthalimido,
--(O-alkyl).sub.r, --O-alkyl-OH, --(O-alkyl).sub.r-OH,
--OR.sup.20c, --SR.sup.20c, --O-alkyl-R.sup.20c,
--S-alkyl-R.sup.20c, --S(.dbd.O)--R.sup.20c,
--S(.dbd.O).sub.2--R.sup.20c, --S(.dbd.O).sub.2--NHR.sup.20c,
--SC(.dbd.O)R.sup.20c, --C(.dbd.O)R.sup.20c, --C(.dbd.O)OR.sup.20c,
--C(.dbd.O)NHR.sup.20c, carbocyclyl optionally substituted with 1-5
R.sup.22; and heterocarbocyclyl optionally substituted with 1-5
R.sup.22; R.sup.20a is C.sub.1-C.sub.20 alkyl, C.sub.2-C.sub.20
alkenyl, or C.sub.2-C.sub.20 alkynyl; wherein said alkyl, alkenyl,
or alkynyl is optionally substituted by one or more halo,
C.sub.1-C.sub.4 alkyl, aryl, heteroaryl or --NHR.sup.20b; R.sup.20c
is carbocyclyl optionally substituted with 1-5 R.sup.22; or
heterocarbocyclyl optionally substituted with 1-5 R.sup.22;
R.sup.22 is selected from the group consisting of: C.sub.1-C.sub.10
alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, phenyl,
halo, haloalkyl, alkoxy, thialkoxy, amino, alkylamino,
dialkylamino, carboxyl, alkyl-OC(.dbd.O)--, alkyl-C(.dbd.O)--,
aryl-OC(.dbd.O)--, alkyl-OC(.dbd.O)NH--, aryl-OC(.dbd.O)NH--,
alkyl-C(.dbd.O)NH--, alkyl-C(.dbd.O)O--, (alkyl-O).sub.r-alkyl,
HO-(alkyl-O).sub.r-alkyl-, --OH, --SH, --CN, --N.sub.3, --CNO,
--CNS, alkyl-S(.dbd.O)--, alkyl-S(.dbd.O).sub.2--,
H.sub.2NS(.dbd.O)--, and H.sub.2NS(.dbd.O).sub.2--; and r is 2, 3,
4, 5, 6, 7, 8, 9, or 10.
2. The compound of claim 1 wherein R.sup.1 is 2-propyl.
3. The compound of claim 2 wherein X is R.sup.AC(.dbd.O)--.
4. The compound of claim 3 wherein R.sup.A is carbocyclyl
optionally substituted with 1-5 R.sup.22.
5. The compound of claim 4 wherein said carbocyclyl is aryl.
6. The compound of claim 5 wherein said aryl is phenyl.
7. The compound of claim 6 wherein R.sup.22 is halo.
8. The compound of claim 7 wherein said halo is chloro.
9. The compound of claim 8 wherein R.sup.A is phenyl substituted
with 1-5 chloro.
10. A compound of Formula (I) ##STR00682## or a pharmaceutically
acceptable salt, stereoisomeric or tautomeric form thereof,
wherein: R.sup.1 is C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl,
C.sub.2-C.sub.8 alkynyl, or C.sub.3-C.sub.7 cycloalkyl; R.sup.2 is
H; Q is --B(OH).sub.2, --B(OR.sup.14).sub.2, or a cyclic boronic
ester wherein said cyclic boronic ester contains from 2 to 20
carbon atoms, and, optionally, a heteroatom which can be N, S, or
O; R.sup.14 is H, C.sub.1-C.sub.4 alkyl, cycloalkyl,
cycloalkylalkyl, aryl, or aralkyl; X is R.sup.AC(.dbd.O)--,
R.sup.ANHC(.dbd.O)--, R.sup.AS(.dbd.O).sub.2--,
R.sup.AOC(.dbd.O)--, R.sup.ASC(.dbd.O)--, or R.sup.A; R.sup.A is
C.sub.1-C.sub.20 alkyl optionally substituted with R.sup.20;
C.sub.2-C.sub.20 alkenyl optionally substituted with R.sup.20;
C.sub.2-C.sub.20 alkynyl optionally substituted with R.sup.20;
carbocyclyl optionally substituted with 1-5 R.sup.21; or
heterocarbocyclyl optionally substituted with 1-5 R.sup.21;
R.sup.20 is selected from the group consisting of: --CN, halo,
haloalkyl-, C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl,
C.sub.2-C.sub.4 alkynyl, --CO.sub.2H, --C(.dbd.O)CO.sub.2H,
--C(.dbd.O)NH.sub.2, --C(.dbd.O)H, --S(.dbd.O)NH.sub.2,
--S(.dbd.O).sub.2NH.sub.2, --OH, --SH, --NH.sub.2, --NH(alkyl),
--N(alkyl).sub.2, --NHC(.dbd.O)NH.sub.2, --NHC(.dbd.O)R.sup.20a,
--NHC(.dbd.O)OR.sup.20a, --OR.sup.20a, --SR.sup.20a,
--S(.dbd.O)R.sup.20a, --S(.dbd.O).sub.2R.sup.20a,
--S(.dbd.O).sub.2--NHR.sup.20a, --SC(.dbd.O)R.sup.20a,
--C(.dbd.O)R.sup.20a, --C(.dbd.O)NHR.sup.20a,
--C(.dbd.O)O--R.sup.20a, --NHS(.dbd.O).sub.2R.sup.20a,
--NHR.sup.20b, phthalimido, --(O-alkyl).sub.r-OH,
--(O-alkyl).sub.r-(O-alkyl), --OR.sup.20c, --SR.sup.20c,
--O-alkyl-R.sup.20c, --S-alkyl-R.sup.20c, --S(.dbd.O)--R.sup.20c,
--S(.dbd.O).sub.2--R.sup.20c, --S(.dbd.O).sub.2--NHR.sup.20c,
--SC(.dbd.O)R.sup.20c, --C(.dbd.O)R.sup.20c, --C(.dbd.O)OR.sup.20c,
--C(.dbd.O)NHR.sup.20c, carbocyclyl optionally substituted with 1-5
R.sup.21; and heterocarbocyclyl optionally substituted with 1-5
R.sup.21; R.sup.20a is C.sub.1-C.sub.20 alkyl, C.sub.2-C.sub.20
alkenyl, or C.sub.2-C.sub.20 alkynyl; wherein said alkyl, alkenyl,
or alkynyl is optionally substituted by one or more halo, OH, CN,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.2-C.sub.8
alkoxyalkoxy, aryl, heteroaryl or --NHR.sup.20b; R.sup.20b is an
amino protecting group; R.sup.20c is carbocyclyl optionally
substituted with 1-5 R.sup.22; or heterocarbocyclyl optionally
substituted with 1-5 R.sup.22; R.sup.21 is selected from the group
consisting of: C.sub.1-C.sub.20 alkyl, C.sub.2-C.sub.20 alkenyl,
C.sub.2-C.sub.20 alkynyl, --OR.sup.21a, --SR.sup.21a, --CN, halo,
haloalkyl, --NH.sub.2, --NH(alkyl), --N(alkyl).sub.2,
--NHC(.dbd.O)O-alkyl, --NHC(.dbd.O)alkyl, --COOH,
--C(.dbd.O)O-alkyl, --C(.dbd.O)alkyl, --C(O)H, --S(.dbd.O)-alkyl,
--S(.dbd.O).sub.2-alkyl, --S(.dbd.O)-aryl, --S(.dbd.O).sub.2-aryl,
carbocyclyl optionally substituted with 1-5 R.sup.22, and
heterocarbocyclyl optionally substituted with 1-5 R.sup.22;
R.sup.21a is H, C.sub.1-C.sub.20 alkyl, C.sub.2-C.sub.20 alkenyl,
C.sub.2-C.sub.20 alkynyl, carbocyclyl or heterocarbocyclyl;
R.sup.22 is selected from the group consisting of: C.sub.1-C.sub.10
alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, phenyl,
halo, haloalkyl, alkoxy, thialkoxy, amino, alkylamino,
dialkylamino, carboxyl, alkyl-OC(.dbd.O)--, alkyl-C(.dbd.O)--,
aryl-OC(.dbd.O)--, alkyl-OC(.dbd.O)NH--, aryl-OC(.dbd.O)NH--,
alkyl-C(.dbd.O)NH--, alkyl-C(.dbd.O)O--, (alkyl-O).sub.r-alkyl,
HO-(alkyl-O).sub.r-alkyl-, --OH, --SH, --CN, --N.sub.3, --CNO,
--CNS, alkyl-S(.dbd.O)--, alkyl-S(.dbd.O).sub.2--,
H.sub.2NS(.dbd.O)--, and H.sub.2NS(.dbd.O).sub.2--; and r is 1, 2,
3, 4, 5, 6, 7, 8, 9, or 10; with the proviso that when Q is a
1,1,2,2-tetramethylethanediol boronic ester, then X is not
aralkyloxycarbonyl.
11. The compound of claim 10 wherein R.sup.1 is 2-propyl.
12. The compound of claim 11 wherein X is R.sup.AC(.dbd.O)-- and
R.sup.A is aryl optionally substituted with 1-3 R.sup.21.
13. The compound of claim 12 wherein R.sup.A is phenyl optionally
substituted with 1-3 R.sup.21.
14. The compound of claim 13 wherein R.sup.21 is halo.
15. The compound of claim 14 wherein said halo is chloro.
16. The compound of claim 15 wherein R.sup.A is phenyl substituted
with 1-3 chloro.
17. The compound of any of claims 1-16 wherein Q is B(OH).sub.2.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 13/020,425, filed Feb. 3, 2011, which is a continuation of U.S.
application Ser. No. 12/496,359, filed Jul. 1, 2009 (now U.S. Pat.
No. 7,915,236, issued Mar. 29, 2011), which is a divisional of U.S.
application Ser. No. 10/918,664, filed Aug. 12, 2004 (now U.S. Pat.
No. 7,576,206, issued Aug. 18, 2009), which claims the benefit of
U.S. Provisional Application No. 60/495,764, filed Aug. 14, 2003,
the disclosures of which are incorporated herein by reference in
their entireties.
FIELD OF THE INVENTION
[0002] The present invention relates to boronic acid and boronic
ester compounds useful as proteasome inhibitors and modulation of
apoptosis.
BACKGROUND OF THE INVENTION
[0003] The proteasome, (also referred to as multicatalytic protease
(MCP), multicatalytic proteinase, multicatalytic proteinase
complex, multicatalytic endopeptidase complex, 20S, 26S, or
ingensin) is a large, multiprotein complex present in both the
cytoplasm and the nucleus of all eukaryotic cells. It is a highly
conserved cellular structure that is responsible for the
ATP-dependent proteolysis of most cellular proteins (Tanaka,
Biochem Biophy. Res. Commun., 1998, 247, 537). The 26S proteasome
consists of a 20S core catalytic complex that is capped at each end
by a 19S regulatory subunit. The archaebacterial 20S proteasome
contains fourteen copies of two distinct types of subunits, .alpha.
and .beta., which form a cylindrical structure consisting of four
stacked rings. The top and bottom rings contain seven
.alpha.-subunits each, while the inner rings contain seven
.beta.-subunits. The more complex eukaryotic 20S proteasome is
composed of about 15 distinct 20-30 kDa subunits and is
characterized by three major activities with respect to peptide
substrates. For example, the proteasome displays tryptic-,
chymotryptic-, and peptidylglutamyl peptide-hydrolytic activities
(Rivett, Biochem. J., 1993, 291, 1 and Orlowski, Biochemistry,
1990, 29, 10289). Further, the proteasome has a unique active site
mechanism which is believed to utilize a threonine residue as the
catalytic nucleophile (Seemuller, et al., Science, 1995, 268,
579).
[0004] The 26S proteasome is able to degrade proteins that have
been marked by the addition of ubiquitin molecules. Typically,
ubiquitin is attached to the .epsilon.-amino groups of lysines in a
multistep process utilizing ATP and E1 (ubiquitin activating) and
E2 (ubiquitin-conjugating) enzymes. Multi-ubiquitinated substrate
proteins are recognized by the 26S proteasome and are degraded. The
multi-ubiquitin chains are generally released from the complex and
ubiquitin is recycled (Goldberg, et al., Nature, 1992, 357,
375).
[0005] Numerous regulatory proteins are substrates for ubiquitin
dependent proteolysis. Many of these proteins function as
regulators of physiological as well as pathophysiological cellular
processes. Alterations in proteasome activity have been implicated
in a number of pathologies including neurodegenerative diseases
such as Parkinson's disease, Alzheimer's disease, as well as
occlusion/ischaemia reperfusion injuries, and aging of the central
nervous system.
[0006] The ubiquitin-proteasome pathway also plays a role in
neoplastic growth. The regulated degradation of proteins such as
cyclins, CDK2 inhibitors, and tumor suppressors is believed to be
important in cell cycle progression and mitosis. A known substrate
of the proteasome is the tumor suppressor p53 which is involved in
several cellular processes (see, e.g., Ko, L. J. Genes Dev., 1996,
10, 1054). Tumor suppressor p53 has been shown to induce apoptosis
in several haematopoietic cell lines (Oren, M., Semin. Cancer
Biol., 1994, 5, 221). Induction of p53 leads to cell growth arrest
in the G1 phase of the cell cycle as well as cell death by
apoptosis. Tumor suppressor p53 degradation is known to be carried
out via the ubiquitin-proteasome pathway, and disrupting p53
degradation by inhibition of the proteasome is a possible mode of
inducing apoptosis.
[0007] The proteasome is also required for activation of the
transcription factor NF-.kappa.B by degradation of its inhibitory
protein, I.kappa.B (Palombella, et al., Cell, 1994, 78, 773).
NF-.kappa.B has a role in maintaining cell viability through the
transcription of inhibitors of apoptosis. Blockade of NF-.kappa.B
activity has been demonstrated to make cells more susceptible to
apoptosis.
[0008] Several inhibitors of the proteolytic activity of the
proteasome have been reported. See, for example, Kisselev, et al.,
Chemistry & Biology, 2001, 8, 739. Lactacystin is a
Streptomyces metabolite that specifically inhibits the proteolytic
activity of the proteasome complex (Fenteany, et al., Science,
1995, 268, 726). This molecule is capable of inhibiting the
proliferation of several cell types (Fenteany, et al., Proc. Natl.
Acad. Sci. USA, 1994, 91, 3358). It has been shown that lactacystin
binds irreversibly, through its .beta.-lactone moiety, to a
threonine residue located at the amino terminus of the
.beta.-subunit of the proteasome.
[0009] Peptide aldehydes have been reported to inhibit the
chymotrypsin-like activity associated with the proteasome
(Vinitsky, et al., Biochemistry, 1992, 31, 9421; Tsubuki, et al.,
Biochem. Biophys. Res. Commun., 1993, 196, 1195; and Rock, et al.,
Cell, 1994, 78, 761). Dipeptidyl aldehyde inhibitors that have
IC.sub.50 values in the 10-100 nM range in vitro (Iqbal, M., et
al., J. Med. Chem., 1995, 38, 2276) have also been reported. A
series of similarly potent in vitro inhibitors from
.alpha..-ketocarbonyl and boronic ester derived dipeptides has also
been reported (Iqbal, et al., Bioorg. Med. Chem. Lett., 1996, 6,
287, U.S. Pat. Nos. 5,614,649; 5,830,870; 5,990,083; 6,096,778;
6,310,057; U.S. Pat. App. Pub. No. 2001/0012854, and WO
99/30707).
[0010] N-terminal peptidyl boronic ester and acid compounds have
been reported previously (U.S. Pat. Nos. 4,499,082 and 4,537,773;
WO 91/13904; Kettner, et al., J. Biol. Chem., 1984, 259(24),
15106). These compounds are reported to be inhibitors of certain
proteolytic enzymes. N-terminal tri-peptide boronic ester and acid
compounds have been shown to inhibit the growth of cancer cells
(U.S. Pat. No. 5,106,948). A broad class of N-terminal tri-peptide
boronic ester and acid compounds and analogs thereof has been shown
to inhibit renin (U.S. Pat. No. 5,169,841).
[0011] Various inhibitors of the peptidase activities of the
proteasome have also been reported. See, e.g., Dick, et al.,
Biochemistry, 1991, 30, 2725; Goldberg, et al., Nature, 1992, 357,
375; Goldberg, Eur. J. Biochem., 1992, 203, 9; Orlowski,
Biochemistry, 1990, 29, 10289; Rivett, et al., Archs. Biochem.
Biophys., 1989, 218, 1; Rivett, et al., J. Biol. Chem., 1989, 264,
12215; Tanaka, et al., New Biol., 1992, 4, 1; Murakami, et al.,
Proc. Natl. Acad. Sci. USA, 1986, 83, 7588; Li et al.,
Biochemistry, 1991, 30, 9709; Goldberg, Eur. J. Biochem., 1992,
203, 9; and Aoyagi, et al., Proteases and Biological Control, Cold
Spring Harbor Laboratory Press (1975), pp. 429-454.
[0012] Stein et al., U.S. patent application Ser. No. 08/212,909,
filed Mar. 15, 1994, report peptide aldehydes useful for reducing
in an animal both the rate of loss of muscle mass and the rate of
intracellular protein breakdown. The compounds are also said to
reduce the rate of degradation of p53 protein in an animal.
Palombella, et al., WO 95/25533, report the use of peptide
aldehydes to reduce the cellular content and activity of
NF-.kappa.B in an animal by contacting cells of the animal with a
peptide aldehyde inhibitor of proteasome function or ubiquitin
conjugation. Goldberg and Rock, WO 94/17816, report the use of
proteasome inhibitors to inhibit MHC-I antigen presentation. Stein,
et al., U.S. Pat. No. 5,693,617 report peptidyl aldehyde compounds
as proteasome inhibitors useful for reducing the rate of
degradation of protein in an animal Inhibition of the 26S and 20S
proteasome by indanone derivatives and a method for inhibiting cell
proliferation using indanone derivatives are reported by Lum et
al., U.S. Pat. No. 5,834,487. Alpha-ketoamide compounds useful for
treating disorders mediated by 20S proteasome in mammals are
reported in Wang et al., U.S. Pat. No. 6,075,150. France, et al.,
WO 00/64863, report the use of 2,4-diamino-3-hydroxycarboxylic acid
derivatives as proteasome inhibitors. Carboxylic acid derivatives
as proteasome inhibitors are reported by Yamaguchi et al., EP
1166781. Ditzel, et al., EP 0 995 757 report bivalent inhibitors of
the proteasome. 2-Aminobenzylstatine derivatives that inhibit
non-covalently the chymotrypsin-like activity of the 20S proteasome
have been reported by Garcia-Echeverria, et al., Bioorg. Med. Chem.
Lett., 2001, 11, 1317.
[0013] Some further proteasome inhibitors can contain boron
moieties. For example, Drexler et al., WO 00/64467, report a method
of selectively inducing apoptosis in activated endothelial cells or
leukemic cells having a high expression level of c-myc by using
tetrapeptidic boronate containing proteasome inhibitors. Furet et
al., WO 02/096933 report 2-[[N-(2-amino-3-(heteroaryl or
aryl)propionyl)aminoacyl]amino]alkylboronic acids and esters for
the therapeutic treatment of proliferative diseases in warm-blooded
animals. U.S. Pat. Nos. 6,083,903; 6,297,217; 5,780,454; 6,066,730;
6,297,217; 6,548,668; U.S. Patent Application Pub. No.
2002/0173488; and WO 96/13266 report boronic ester and acid
compounds and a method for reducing the rate of degradation of
proteins. A method for inhibiting viral replication using certain
boronic acids and esters is also reported in U.S. Pat. No.
6,465,433 and WO 01/02424. Pharmaceutically acceptable compositions
of boronic acids and novel boronic acid anhydrides and boronate
ester compounds are reported by Plamondon, et al., U.S. Patent
Application Pub. No. 2002/0188100. A series of di- and tripeptidyl
boronic acids are shown to be inhibitors of 20S and 26S proteasome
in Gardner, et al., Biochem. J., 2000, 346, 447.
[0014] Other boron-containing peptidyl and related compounds are
reported in U.S. Pat. Nos. 5,250,720; 5,242,904; 5,187,157;
5,159,060; 5,106,948; 4,963,655; 4,499,082; and WO 89/09225,
WO/98/17679, WO 98/22496, WO 00/66557, WO 02/059130, WO 03/15706,
WO 96/12499, WO 95/20603, WO 95/09838, WO 94/25051, WO 94/25049, WO
94/04653, WO 02/08187, EP 632026, and EP 354522.
[0015] A great interest exists, as evidenced by the above
references, in drugs which can modulate proteasome activity. For
example, molecules capable of inhibiting proteasome activity can
arrest or delay cancer progression by interfering with the ordered
degradation of cell cycle proteins or tumor suppressors.
Accordingly, there is an ongoing need for new and/or improved
inhibitors of proteasome.
SUMMARY OF THE INVENTION
[0016] The present invention is directed to novel boronic acid and
boronic ester compounds useful as proteasome inhibitors and
modulation of apoptosis. The subject invention also comprises
methods for inhibition of multicatalytic protease ("MCP")
associated with certain disorders, including the treatment of
muscle wasting disorders.
[0017] In one embodiment are provided compounds having Formula
(I):
##STR00001##
wherein constituent members are defined infra, as well as preferred
constituent members.
[0018] In another embodiment the present invention provides a
pharmaceutical composition comprising a compound of Formula (I) and
a pharmaceutically acceptable carrier.
[0019] In another embodiment the present invention provides a
method of inhibiting activity of proteasome comprising contacting a
compound of Formula (I) with said proteasome.
[0020] In another embodiment the present invention provides a
method of treating cancer comprising administering to a mammal
having or predisposed to said cancer a therapeutically effective
amount of a compound of Formula (I).
[0021] In another embodiment the present invention provides a
method of treating cancer treating cancer comprising administering
to a mammal having or predisposed to said cancer a therapeutically
effective amount of a compound of Formula (I), and wherein said
cancer is selected from skin, prostate, colorectal, pancreas,
kidney, ovary, mammary, liver, tongue, lung, and smooth muscle
tissue.
[0022] In another embodiment the present invention provides a
method of treating cancer comprising administering to a mammal
having or predisposed to said cancer a therapeutically effective
amount of a compound of Formula (I), and wherein said cancer is
selected from leukemia, lymphoma, non-Hodgkin lymphoma, myeloma,
and multiple myeloma.
[0023] In another embodiment the present invention provides a
method of treating cancer comprising administering to a mammal
having or predisposed to said cancer a therapeutically effective
amount of a compound of Formula (I) in combination with one or more
antitumor or anticancer agent and/or radiotherapy.
[0024] In another embodiment the present invention provides a
method of inhibiting activity of transcription factor NF-.kappa.B
comprising contacting I.kappa.B, the inhibitor of transcription
factor NF-.kappa.B, with a compound of Formula (I).
[0025] In another embodiment, the present invention provides
processes for preparing a compound of Formula (II):
##STR00002##
wherein constituent members are defined herein, by reacting a diol
of Formula (II-b):
##STR00003##
with an appropriate trialkoxyborane of Formula (II-a):
##STR00004##
wherein constituent members are defined herein; for a time and
under conditions suitable for forming an intermediate of Formula
(II-c):
##STR00005##
and reacting the intermediate of Formula (II-c) with either i) a
reagent of formula R.sup.1CH.sub.2MX.sup.hal, wherein M is a metal
and X.sup.hal is a halogen atom, or ii) a reagent of formula
R.sup.1CH.sub.2Li, for a time and under conditions suitable for
forming the compound of Formula (II).
[0026] These and other features of the compounds will be set forth
in expanded form as the disclosure continues.
DESCRIPTION OF EMBODIMENTS OF THE INVENTION
[0027] The present invention provides, inter alia, compounds that
can inhibit proteasome activity and be used for the treatment of
diseases or disorders related to proteasome activity. Compounds of
the invention include compounds of Formula (I)
##STR00006##
or pharmaceutically acceptable salt, stereoisomeric or tautomeric
form thereof, wherein: [0028] R.sup.1 is C.sub.1-C.sub.8 alkyl,
C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, or
C.sub.3-C.sub.7 cycloalkyl; [0029] R.sup.2 is H,
--(CH.sub.2).sub.aCH.sub.2NHC(.dbd.NR.sup.4)NH--Y,
--(CH.sub.2).sub.bCH.sub.2CONR.sup.5R.sup.6,
--(CH.sub.2).sub.cCH.sub.2N(R.sup.4)CONH.sub.2,
--(CH.sub.2).sub.dCH(R.sup.7)NR.sup.9R.sup.10, or
--(CH.sub.2).sub.eCH(R.sup.7)ZR.sup.8; [0030] a, b, and c are each,
independently, 0, 1, 2, 3, 4, 5, or 6; [0031] d and e are each,
independently, 0, 1, 2, 3, or 4; [0032] R.sup.4 is H or
C.sub.1-C.sub.10 alkyl; [0033] R.sup.5 and R.sup.6 are each,
independently, H, C.sub.1-C.sub.10 alkyl, carbocyclyl,
heterocarbocyclyl, or an amino protecting group; [0034]
alternatively, R.sup.5 and R.sup.6 together with the N atom to
which they are attached form a heterocarbocyclyl group; [0035]
R.sup.7 is H or C.sub.1-C.sub.10 alkyl; [0036] R.sup.8 is H,
C.sub.1-C.sub.10 alkyl, alkyl-S(.dbd.O).sub.2--,
aryl-S(.dbd.O).sub.2--, H.sub.2NS(.dbd.O).sub.2--, --SO.sub.3H, or
a protecting group; [0037] R.sup.9 is H, C.sub.1-C.sub.10 alkyl,
carbocyclyl, or heterocarbocyclyl; [0038] R.sup.10 is H,
C.sub.1-C.sub.10 alkyl, carbocyclyl, heterocarbocyclyl,
C.sub.1-C.sub.10 alkyl-C(.dbd.O)--, C.sub.2-C.sub.10
alkenyl-C(.dbd.O)--, C.sub.2-C.sub.10 alkynyl-C(.dbd.O)--,
carbocyclyl-C(.dbd.O)--, heterocarbocyclyl-C(.dbd.O)--,
carbocyclylalkyl-C(.dbd.O)--, heterocarbocyclylalkyl-C(.dbd.O)--,
C.sub.1-C.sub.10 alkyl-S(.dbd.O).sub.2--,
carbocyclyl-S(.dbd.O).sub.2--, heterocarbocyclyl-S(.dbd.O).sub.2--,
carbocyclylalkyl-S(.dbd.O).sub.2--,
heterocarbocyclylalkyl-S(.dbd.O).sub.2--, C.sub.1-C.sub.10
alkyl-NHC(.dbd.O)--, carbocyclyl-NHC(.dbd.O)--,
heterocarbocyclyl-NHC(.dbd.O)--, carbocyclylalkyl-NHC(.dbd.O)--,
heterocarbocyclylalkyl-NHC(.dbd.O)--, C.sub.1-C.sub.10
alkyl-OC(.dbd.O)--, carbocyclyl-OC(.dbd.O)--,
heterocarbocyclyl-OC(.dbd.O)--, carbocyclylalkyl-OC(.dbd.O)--,
heterocarbocyclylalkyl-OC(.dbd.O)--, C.sub.1-C.sub.10
alkyl-NH--C(.dbd.O)--NHS(.dbd.O).sub.2--,
carbocyclyl-NH--C(.dbd.O)--NHS(.dbd.O).sub.2--,
heterocarbocyclyl-NH--C(.dbd.O)--NHS(.dbd.O).sub.2--,
C.sub.1-C.sub.10 alkyl-S(.dbd.O).sub.2--NH--C(.dbd.O)--,
carbocyclyl-S(.dbd.O).sub.2--NH--C(.dbd.O)--,
heterocarbocyclyl-S(.dbd.O).sub.2--NH--C(.dbd.O)--, or an amino
protecting group; wherein R.sup.10 is optionally substituted with
1, 2 or 3, R.sup.23; [0039] alternatively, R.sup.9 and R.sup.10
together with the N atom to which they are attached form a
heterocarbocyclyl group optionally substituted with 1, 2 or 3
R.sup.23; [0040] Y is H, --CN, --NO.sub.2,
--S(.dbd.O).sub.2R.sup.11, or a guanidino protecting group; [0041]
R.sup.11 is C.sub.1-C.sub.6 alkyl, aryl, or NR.sup.12R.sup.13;
[0042] R.sup.12 and R.sup.13 are, independently, H,
C.sub.1-C.sub.10 alkyl, carbocyclyl, heterocarbocyclyl, or an amino
protecting group; [0043] alternatively, R.sup.12 and R.sup.13
together with the N atom to which they are attached form a
heterocarbocyclyl group; [0044] Z is O, S, Se, or Te; [0045] Q is
--B(OH).sub.2, --B(OR.sup.14).sub.2, or a cyclic boronic ester
wherein said cyclic boronic ester contains from 2 to 20 carbon
atoms, and, optionally, a heteroatom which can be N, S, or O;
[0046] R.sup.14 is H, C.sub.1-C.sub.4 alkyl, cycloalkyl,
cycloalkylalkyl, aryl, or aralkyl; [0047] X is R.sup.AC(.dbd.O)--,
R.sup.ANHC(.dbd.O)--, R.sup.AS(.dbd.O).sub.2--, R.sup.AC(.dbd.O)--,
R.sup.ASC(.dbd.O)--, or R.sup.A; [0048] R.sup.A is C.sub.1-C.sub.20
alkyl optionally substituted with R.sup.20; C.sub.2-C.sub.20
alkenyl optionally substituted with R.sup.20; C.sub.2-C.sub.20
alkynyl optionally substituted with R.sup.20; carbocyclyl
optionally substituted with 1-5 R.sup.21; or heterocarbocyclyl
optionally substituted with 1-5 R.sup.21; [0049] R.sup.20 is
selected from the group consisting of: [0050] --CN, halo,
haloalkyl-, C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl,
C.sub.2-C.sub.4 alkynyl, --CO.sub.2H, --C(.dbd.O)CO.sub.2H,
--C(.dbd.O)NH.sub.2, --C(.dbd.O)H, --S(.dbd.O)NH.sub.2,
--S(.dbd.O).sub.2NH.sub.2, --OH, --SH, --NH.sub.2, --NH(alkyl),
--N(alkyl).sub.2, --NHC(.dbd.O)NH.sub.2, --NHC(.dbd.O)R.sup.20a,
--NHC(.dbd.O)OR.sup.20a, --OR.sup.20a, --SR.sup.20a,
--S(.dbd.O)R.sup.20a, --S(.dbd.O).sub.2R.sup.20a,
--S(.dbd.O).sub.2--NHR.sup.20a, --SC(.dbd.O)R.sup.20a,
--C(.dbd.O)R.sup.20a, --C(.dbd.O)NHR.sup.20a,
--C(.dbd.O)O--R.sup.20a, --NHS(.dbd.O).sub.2R.sup.20a,
--NHR.sup.20b, phthalimido, --(O-alkyl).sub.r-OH,
--(O-alkyl).sub.r-(O-alkyl), --OR.sup.20c, --SR.sup.20c,
--O-alkyl-R.sup.20c, --S-alkyl-R.sup.20c, --S(.dbd.O)--R.sup.20c,
--S(.dbd.O).sub.2--R.sup.20c, --S(.dbd.O).sub.2--NHR.sup.20c,
--SC(.dbd.O)R.sup.20c, --C(.dbd.O)OR.sup.20c,
--C(.dbd.O)NHR.sup.20c, carbocyclyl optionally substituted with 1-5
R.sup.21; and heterocarbocyclyl optionally substituted with 1-5
R.sup.21; [0051] R.sup.20a is C.sub.1-C.sub.20 alkyl,
C.sub.2-C.sub.20 alkenyl, or C.sub.2-C.sub.20 alkynyl; wherein said
alkyl, alkenyl, or alkynyl is optionally substituted by one or more
halo, OH, CN, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
C.sub.2-C.sub.8 alkoxyalkoxy, aryl, heteroaryl or --NHR.sup.20b;
[0052] R.sup.20b is an amino protecting group; [0053] R.sup.20c is
carbocyclyl optionally substituted with 1-5 R.sup.22; or
heterocarbocyclyl optionally substituted with 1-5 R.sup.22; [0054]
R.sup.21 is selected from the group consisting of: [0055]
C.sub.1-C.sub.20 alkyl, C.sub.2-C.sub.20 alkenyl, C.sub.2-C.sub.20
alkynyl, --OR.sup.21a, SR.sub.21a, --CN, halo, haloalkyl,
--NH.sub.2, --NH(alkyl), --N(alkyl).sub.2, --NHC(.dbd.O)O-alkyl,
--NHC(.dbd.O)alkyl, --COOH, --C(.dbd.O)O-alkyl, --C(.dbd.O)alkyl,
--C(O)H, --S(.dbd.O)-alkyl, --S(.dbd.O).sub.2-alkyl,
--S(.dbd.O)-aryl, --S(.dbd.O).sub.2-aryl, carbocyclyl optionally
substituted with 1-5 R.sup.22, and heterocarbocyclyl optionally
substituted with 1-5 R.sup.22; [0056] R.sup.21a is H,
C.sub.1-C.sub.20 alkyl, C.sub.2-C.sub.20 alkenyl, C.sub.2-C.sub.20
alkynyl, carbocyclyl or heterocarbocyclyl; [0057] R.sup.22 is
selected from the group consisting of: [0058] C.sub.1-C.sub.10
alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, phenyl,
halo, haloalkyl, alkoxy, thialkoxy, amino, alkylamino,
dialkylamino, carboxyl, alkyl-OC(.dbd.O)--, alkyl-C(.dbd.O)--,
aryl-OC(.dbd.O)--, alkyl-OC(.dbd.O)NH--, aryl-OC(.dbd.O)NH--,
alkyl-C(.dbd.O)NH--, alkyl-C(.dbd.O)O--, (alkyl-O).sub.r-alkyl,
HO-(alkyl-O).sub.r-alkyl-, --OH, --SH, --CN, --N.sub.3, --CNO,
--CNS, alkyl-S(.dbd.O)--, alkyl-S(.dbd.O).sub.2--,
H.sub.2NS(.dbd.O)--, and H.sub.2NS(.dbd.O).sub.2--; [0059] R.sup.23
is selected from the group consisting of: [0060] C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, F, Cl, Br,
I, haloalkyl, --NH.sub.2, --NHR.sup.23a, --N(R.sup.23a).sub.2,
--N.sub.3, --NO.sub.2, --CN, --CNO, --CNS, --C(.dbd.O)OR.sup.23a,
--C(.dbd.O)R.sup.23a, --OC(.dbd.O)R.sup.23a,
--N(R.sup.23a)C(.dbd.O)R.sup.23a,
--N(R.sup.23a)C(.dbd.O)OR.sup.23a, --C(.dbd.O)N(R.sup.23a).sub.2,
ureido, --OR.sup.23a, --SR.sup.23a, --S(.dbd.O)--(C.sub.1-C.sub.6
alkyl), --S(.dbd.O).sub.2--(C.sub.1-C.sub.6 alkyl),
--S(.dbd.O)-aryl, --S(.dbd.O).sub.2-aryl,
--S(.dbd.O).sub.2--N(R.sup.23a).sub.2; carbocyclyl optionally
substituted with 1-5 R.sup.24; and heterocarbocyclyl optionally
substituted with 1-5 R.sup.24; [0061] R.sup.23a is H or
C.sub.1-C.sub.6 alkyl; [0062] alternatively, two R.sup.23a may be
combined, together with the N atom to which they are attached, to
form a 5 to 7 membered heterocyclic group; and [0063] R.sup.24 is
selected from the group consisting of: [0064] C.sub.1-C.sub.4
alkyl, C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 alkynyl, phenyl,
halo, haloalkyl, alkoxy, thialkoxy, amino, alkylamino,
dialkylamino, carboxyl, alkyl-OC(.dbd.O)--, alkyl-C(.dbd.O)--,
aryl-OC(.dbd.O)--, alkyl-OC(.dbd.O)NH--, aryl-OC(.dbd.O)NH--,
alkyl-C(.dbd.O)NH--, alkyl-C(.dbd.O)O--, (alkyl-O).sub.r-alkyl,
HO-(alkyl-O).sub.r-alkyl-, --OH, --SH, --CN, --N.sub.3, --CNO,
--CNS, alkyl-S(.dbd.O)--, alkyl-S(.dbd.O).sub.2--,
H.sub.2NS(.dbd.O)--, and H.sub.2NS(.dbd.O).sub.2--; and [0065] r is
1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; [0066] with the proviso that when
Q is a 1,1,2,2-tetramethylethanediol boronic ester, then X is not
aralkyloxycarbonyl; [0067] with the proviso that when Q is a
1,1,2,2-tetramethylethanediol boronic ester, and R.sup.1 is
cycloalkyl, then R.sup.2 is not --CH.sub.2CONH.sub.2; and [0068]
with the proviso that when X is R.sup.AC(.dbd.O)--, R.sup.A is a
C.sub.4-C.sub.15 straight-chained alkyl substituted with R.sup.20,
and R.sup.20 is --CN, --CO.sub.2H, --C(.dbd.O)O--R.sup.20a,
--NHS(.dbd.O).sub.2R.sup.20a, --NHC(.dbd.O)R.sup.20a,
--NHR.sup.20b, or phthalimido; then R.sup.2 is not
--(CH.sub.2).sub.aCH.sub.2NHC(.dbd.NR.sup.4)NH--Y, wherein Y is H,
--CN, --NO.sub.2, or a guanidino protecting group.
[0069] In further embodiments, when R.sup.2 is
--(CH.sub.2).sub.eCH(R.sup.7)ZR.sup.8, e is 0, R.sup.7 is H,
R.sup.8 is C.sub.1-C.sub.10 alkyl and X is R.sup.AC(.dbd.O)--, then
R.sup.A is not aminoalkyl-, alkylaminoalkyl-, dialkylaminoalkyl-,
or ureidoalkyl-.
[0070] In some embodiments, R.sup.1 can be C.sub.1-C.sub.4 alkyl,
and in further embodiments, R.sup.1 can be propyl, such as
2-propyl.
[0071] In some embodiments, R.sup.2 can be
--(CH.sub.2).sub.aCH.sub.2NHC(.dbd.NR.sup.4)NH--Y,
--(CH.sub.2).sub.bCH.sub.2CONR.sup.5R.sup.6,
--(CH.sub.2).sub.cCH.sub.2N(R.sup.4)CONH.sub.2,
--(CH.sub.2).sub.dCH(R.sup.7)NR.sup.9R.sup.10, or
--(CH.sub.2).sub.eCH(R.sup.7)ZR.sup.8.
[0072] In some embodiments, R.sup.2 is
--(CH.sub.2).sub.aCH.sub.2NHC(.dbd.NR.sup.4)NH--Y and a is 1, 2, 3,
4, or 5.
[0073] In some embodiments, R.sup.2 is
--(CH.sub.2).sub.aCH.sub.2NHC(.dbd.NR.sup.4)NH--Y and a is 2.
[0074] In some embodiments, R.sup.2 is
--CH.sub.2CH.sub.2CH.sub.2NHC(.dbd.NR.sup.4)NH--Y.
[0075] In some embodiments, R.sup.2 is
--(CH.sub.2).sub.dCH(R.sup.7)NR.sup.9R.sup.10 and d is 0, 1, or
2.
[0076] In some embodiments, R.sup.2 is
--(CH.sub.2).sub.dCH(R.sup.7)NR.sup.9R.sup.10 and d is 0.
[0077] In some embodiments, R.sup.2 is
--(CH.sub.2).sub.dCH(R.sup.7)NR.sup.9R.sup.10 and R.sup.9 is H.
[0078] In some embodiments, R.sup.2 is
--(CH.sub.2).sub.dCH(R.sup.7)NR.sup.9R.sup.10.
[0079] In some embodiments, R.sup.2 is
--CH(R.sup.7)NR.sup.9R.sup.10.
[0080] In some embodiments, R.sup.2 is
--CH.sub.2NH--C(.dbd.O)OCH.sub.2(C.sub.6H.sub.5).
[0081] In some embodiments, R.sup.2 is
--(CH.sub.2).sub.eCH(R.sup.7)ZR.sup.8 and e is 0, 1, or 2.
[0082] In some embodiments, R.sup.2 is
--(CH.sub.2).sub.eCH(R.sup.7)ZR.sup.8 and e is 0.
[0083] In some embodiments, R.sup.2 is
--(CH.sub.2).sub.eCH(R.sup.7)ZR.sup.8.
[0084] In some embodiments, R.sup.2 is --CH(R.sup.7)ZR.sup.8.
[0085] In further embodiments, Z is O.
[0086] In further embodiments, Q has Formula (II-a):
##STR00007##
wherein D, R.sup.15a, R.sup.15b, R.sup.15c, R.sup.15d, p and q are
defined herein below.
[0087] In further embodiments, Q is B(OH).sub.2 or a cyclic boronic
ester wherein said cyclic boronic ester contains from 6 to 10
carbon atoms and contains at least one cycloalkyl moiety.
[0088] In further embodiments Q is B(OH).sub.2.
[0089] In further embodiments Q is pinanediol boronic ester.
[0090] In further embodiments Q is bicyclohexyl-1,1'-diol boronic
ester.
[0091] In further embodiments, Q is
1,2-dicyclohexyl-ethane-1,2-diol boronic ester.
[0092] Alternatively, in some embodiments, Q is --B(OH).sub.2,
--B(OR.sup.14).sub.2,
##STR00008##
[0093] wherein:
[0094] R.sup.14, R.sup.15a, R.sup.15b, R.sup.15c, R.sup.15d, W,
W.sup.1, p and q are as defined hereinbelow.
[0095] In further embodiments Q is:
##STR00009##
W is a substituted or unsubstituted C.sub.4-C.sub.10 cycloalkyl
ring.
[0096] In some embodiments, X is R.sup.AC(.dbd.O)--.
[0097] In some embodiments, X is R.sup.ANHC(.dbd.O)--.
[0098] In some embodiments, X is R.sup.AS(O).sub.2--.
[0099] In some embodiments, R.sup.A is C.sub.1-C.sub.14 alkyl
substituted by --(O-alkyl).sub.r-OH or
--(O-alkyl).sub.r-(O-alkyl), wherein r is 1, 2, 3, 4, or 5.
[0100] In some embodiments, R.sup.A is C.sub.1-C.sub.14 alkyl
substituted by --(O-alkyl).sub.r-OH or
--(O-alkyl).sub.r-(O-alkyl), wherein r is 1, 2 or 3.
[0101] In some embodiments, R.sup.A comprises at least one
--CH.sub.2CH.sub.2O-- group.
[0102] In some embodiments, R.sup.A is
--CH.sub.2(OCH.sub.2CH.sub.2).sub.rOCH.sub.3.
[0103] In some embodiments, R.sup.A is
--CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2OCH.sub.3 or
--CH.sub.2OCH.sub.2CH.sub.2OCH.sub.3.
[0104] In some embodiments, R.sup.A is aryl or heteroaryl each
optionally substituted with 1-5 R.sup.21.
[0105] In some embodiments, R.sup.A is cycloalkyl or
heterocycloalkyl each optionally substituted with 1-5 R.sup.21.
[0106] In some embodiments, R.sup.A is C.sub.1-C.sub.20 alkyl;
C.sub.2-C.sub.20 alkenyl; or C.sub.2-C.sub.20 alkynyl, each
optionally substituted with R.sup.20.
[0107] In some embodiments, R.sup.A is C.sub.1-C.sub.20 alkyl;
C.sub.2-C.sub.20 alkenyl; or C.sub.2-C.sub.20 alkynyl, each
substituted with a carbocyclyl group or a heterocarbocyclyl group
wherein said carbocyclyl group or heterocarbocyclyl group is
optionally substituted with 1, 2 or 3 R.sup.21.
[0108] In some embodiments, R.sup.A is C.sub.1-C.sub.20 alkyl;
C.sub.2-C.sub.20 alkenyl; or C.sub.2-C.sub.20 alkynyl, each
substituted with an aryl group wherein said aryl group is
optionally substituted with 1, 2 or 3 R.sup.21.
[0109] In some embodiments, R.sup.A is C.sub.1-C.sub.20 alkyl;
C.sub.2-C.sub.20 alkenyl; or C.sub.2-C.sub.20 alkynyl, each
substituted with an heteroaryl group wherein said heteroaryl group
is optionally substituted with 1, 2 or 3 R.sup.21.
[0110] In some embodiments, R.sup.A is C.sub.1-C.sub.20 alkyl;
C.sub.2-C.sub.20 alkenyl; or C.sub.2-C.sub.20 alkynyl, each
substituted with an cycloalkyl group wherein said cycloalkyl group
is optionally substituted with 1, 2 or 3 R.sup.21.
[0111] In some embodiments, R.sup.A is C.sub.1-C.sub.20 alkyl;
C.sub.2-C.sub.20 alkenyl; or C.sub.2-C.sub.20 alkynyl, each
substituted with an heterocycloalkyl group wherein said
heterocycloalkyl group is optionally substituted with 1, 2 or 3
R.sup.21.
[0112] In some embodiments, R.sup.A is C.sub.1-C.sub.20 alkyl;
C.sub.2-C.sub.20 alkenyl; or C.sub.2-C.sub.20 alkynyl, each
optionally substituted with R.sup.20, wherein R.sup.20 is selected
from CN, halo, haloalkyl, --CO.sub.2H, --C(.dbd.O)CO.sub.2H,
--C(.dbd.O)NH.sub.2, --C(.dbd.O)H, --S(O)NH.sub.2,
--S(O).sub.2NH.sub.2, --OH, --SH, --NH.sub.2, --NH(alkyl),
--N(alkyl).sub.2, --NHC(.dbd.O)NH.sub.2, --NHC(.dbd.O)R.sup.20a,
--NHC(.dbd.O)OR.sup.20a, --OR.sup.20a, --SR.sup.20a,
--S(O)R.sup.20a, --S(O).sub.2R.sup.20a, --S(O).sub.2--NHR.sup.20a,
--SC(.dbd.O)R.sup.20a, --C(.dbd.O)R.sup.20a,
--C(.dbd.O)NHR.sup.20a, --C(.dbd.O)O--R.sup.20a,
--NHS(O).sub.2R.sup.20a, --NHR.sup.20b, phthalimido, --(O-alkyl),
--(O-alkyl).sub.r-OH, --(O-alkyl).sub.r-(O-alkyl), --OR.sup.20c,
--SR.sup.20c, --O-alkyl-R.sup.20c, --S-alkyl-R.sup.20c,
--S(O)--R.sup.20c, --S(O).sub.2--R.sup.20c,
--S(O).sub.2--NHR.sup.20c, --SC(.dbd.O)R.sup.20e,
--C(.dbd.O)R.sup.20c, --C(.dbd.O)OR.sup.20c, and
--C(.dbd.O)NHR.sup.20c.
[0113] In some embodiments, R.sup.2 is H and X is
(O-alkyl)--(O-alkyl).sub.r-(C.sub.1-C.sub.14 alkyl)-C(.dbd.O)-- or
HO-(alkyl-O).sub.r--(C.sub.1-C.sub.14 alkyl)-C(.dbd.O)--.
[0114] In some embodiments X is R.sup.AC(.dbd.O)-- and R.sup.A is
C.sub.4-C.sub.16 alkyl.
[0115] In some embodiments X is R.sup.AC(.dbd.O)-- and R.sup.A is
aryl optionally substituted with 1-3 R.sup.21.
[0116] In some embodiments X is R.sup.AC(.dbd.O)-- and R.sup.A is
heterocarbocyclyl group optionally substituted with 1-3
R.sup.21.
[0117] In some embodiments X is R.sup.AC(.dbd.O)--; R.sup.A is
phenyl substituted with one R.sup.21; and R.sup.21 is phenoxy.
[0118] In some embodiments X is R.sup.AC(.dbd.O)--, R.sup.A is
C.sub.1-C.sub.4 alkyl substituted with R.sup.20, and R.sup.20 is
aryl optionally substituted with 1-3 R.sup.21; and in yet further
embodiments aryl is substituted by at least one halo.
[0119] In some embodiments X is R.sup.AC(.dbd.O)--; R.sup.A is
C.sub.1-C.sub.14 alkyl substituted with R.sup.20; and R.sup.20 is
--OR.sup.20a or --OR.sup.20c.
[0120] In some embodiments X is R.sup.AC(.dbd.O)--; R.sup.A is
C.sub.1-C.sub.14 alkyl substituted with R.sup.20; and R.sup.20 is
heterocarbocyclyl optionally substituted with 1-3 R.sup.21.
[0121] In some embodiments X is R.sup.AS(O).sub.2-- and R.sup.A is
C.sub.3-C.sub.16 alkyl.
[0122] In some embodiments the present invention provides compounds
of Formula (I) wherein the stereochemistry is of Formula (I-s):
##STR00010##
or pharmaceutically acceptable salt form thereof
[0123] In some embodiments, the present invention provides
compounds of Formula (I)
##STR00011##
or pharmaceutically acceptable salt, stereoisomeric or tautomeric
form thereof, wherein: [0124] R.sup.1 is C.sub.1-C.sub.8 alkyl,
C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, or
C.sub.3-C.sub.7 cycloalkyl; [0125] R.sup.2 is H,
--(CH.sub.2).sub.aCH.sub.2NHC(.dbd.NR.sup.4)NH--Y,
--(CH.sub.2).sub.bCH.sub.2CONR.sup.5R.sup.6,
--(CH.sub.2).sub.cCH.sub.2N(R.sup.4)CONH.sub.2,
--(CH.sub.2).sub.dCH(R.sup.7)NR.sup.9R.sup.10, or
--(CH.sub.2).sub.eCH(R.sup.7)ZR.sup.8; [0126] a, b, and c are each,
independently, 0, 1, 2, 3, 4, 5, or 6; [0127] d and e are each,
independently, 0, 1, 2, 3, or 4; [0128] R.sup.4 is H or
C.sub.1-C.sub.10 alkyl; [0129] R.sup.5 and R.sup.6 are each,
independently, H, C.sub.1-C.sub.10 alkyl, carbocyclyl,
heterocarbocyclyl, or an amino protecting group; [0130]
alternatively, R.sup.5 and R.sup.6 together with the N atom to
which they are attached form a heterocarbocyclyl group; [0131]
R.sup.7 is H or C.sub.1-C.sub.10 alkyl; [0132] R.sup.8 is H,
C.sub.1-C.sub.10 alkyl, alkyl-S(.dbd.O).sub.2--,
aryl-S(.dbd.O).sub.2--, H.sub.2NS(.dbd.O).sub.2--, --SO.sub.3H, or
a protecting group; [0133] R.sup.9 is H, C.sub.1-C.sub.10 alkyl,
carbocyclyl, or heterocarbocyclyl; [0134] R.sup.10 is H,
C.sub.1-C.sub.10 alkyl, carbocyclyl, heterocarbocyclyl,
C.sub.1-C.sub.10 alkyl-C(.dbd.O)--, carbocyclyl-C(.dbd.O)--,
heterocarbocyclyl-C(.dbd.O)--, carbocyclylalkyl-C(.dbd.O)--,
heterocarbocyclylalkyl-C(.dbd.O)--, C.sub.1-C.sub.10
alkyl-S(.dbd.O).sub.2--, carbocyclyl-S(.dbd.O).sub.2--,
heterocarbocyclyl-S(.dbd.O).sub.2--,
carbocyclylalkyl-S(.dbd.O).sub.2--,
heterocarbocyclylalkyl-S(.dbd.O).sub.2--, C.sub.1-C.sub.10
alkyl-NHC(.dbd.O)--, carbocyclyl-NHC(.dbd.O)--,
heterocarbocyclyl-NHC(.dbd.O)--, carbocyclylalkyl-NHC(.dbd.O)--,
heterocarbocyclylalkyl-NHC(.dbd.O)--, C.sub.1-C.sub.10
alkyl-OC(.dbd.O)--, carbocyclyl-OC(.dbd.O)--,
heterocarbocyclyl-OC(.dbd.O)--, carbocyclylalkyl-OC(.dbd.O)--,
heterocarbocyclylalkyl-OC(.dbd.O)--, or an amino protecting group;
wherein R.sup.10 is optionally substituted with 1, 2, or 3
R.sup.23; [0135] alternatively, R.sup.9 and R.sup.10 together with
the N atom to which they are attached form a heterocarbocyclyl
group; [0136] Y is --H, --CN, --NO.sub.2,
--S(.dbd.O).sub.2R.sup.11, or a guanidino protecting group; [0137]
R.sup.11 is C.sub.1-C.sub.6 alkyl, aryl, or NR.sup.12R.sup.13;
[0138] R.sup.12 and R.sup.13 are, independently, H,
C.sub.1-C.sub.10 alkyl, carbocyclyl, heterocarbocyclyl, or an amino
protecting group; [0139] alternatively, R.sup.12 and R.sup.13
together with the N atom to which they are attached form a
heterocarbocyclyl group; [0140] Z is O, S, Se, or Te; [0141] Q is
--B(OH).sub.2, --B(OR.sup.14).sub.2, or a cyclic boronic ester
wherein said cyclic boronic ester contains from 2 to 20 carbon
atoms, and, optionally, a heteroatom which can be N, S, or O;
[0142] R.sup.14 is H, C.sub.1-C.sub.4 alkyl, cycloalkyl,
cycloalkylalkyl, aryl, or aralkyl; [0143] X is R.sup.AC(.dbd.O)--,
R.sup.ANHC(.dbd.O)--, R.sup.AS(.dbd.O).sub.2--, R.sup.AC(.dbd.O)--,
R.sup.ASC(.dbd.O)--, or R.sup.A; [0144] R.sup.A is C.sub.1-C.sub.20
alkyl optionally substituted with R.sup.20; C.sub.2-C.sub.20
alkenyl optionally substituted with R.sup.20; C.sub.2-C.sub.20
alkynyl optionally substituted with R.sup.20; carbocyclyl
optionally substituted with 1-5 R.sup.21; or heterocarbocyclyl
optionally substituted with 1-5 R.sup.21; [0145] R.sup.20 is
selected from the group consisting of: [0146] --CN, halo,
haloalkyl-, C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl,
C.sub.2-C.sub.4 alkynyl, --CO.sub.2H, --C(.dbd.O)CO.sub.2H,
--C(.dbd.O)NH.sub.2, --C(.dbd.O)H, --S(.dbd.O)NH.sub.2,
--S(.dbd.O).sub.2NH.sub.2, --OH, --SH, --NH.sub.2, --NH(alkyl),
--N(alkyl).sub.2, --NHC(.dbd.O)NH.sub.2, --NHC(.dbd.O)R.sup.20a,
--NHC(.dbd.O)OR.sup.20a, --OR.sup.20a, --SR.sup.20a,
--S(.dbd.O)R.sup.20a, --S(.dbd.O).sub.2R.sup.20a,
--S(.dbd.O).sub.2--NHR.sup.20a, --SC(.dbd.O)R.sup.20a,
--C(.dbd.O)R.sup.20a, --C(.dbd.O)NHR.sup.20a,
--C(.dbd.O)O--R.sup.20a, --NHS(.dbd.O).sub.2R.sup.20a,
--NHR.sup.20b, phthalimido, --(--O-alkyl).sub.r, --O-alkyl-OH,
--(O-alkyl).sub.r-OH, --OR.sup.20c, --SR.sup.20c,
--O-alkyl-R.sup.20c, --S-alkyl-R.sup.20c, --S(.dbd.O)--R.sup.20c,
--S(.dbd.O).sub.2--R.sup.20c, --S(.dbd.O).sub.2--NHR.sup.20c,
--SC(.dbd.O)R.sup.20c, --C(.dbd.O)R.sup.20c, --C(.dbd.O)OR.sup.20c,
--C(.dbd.O)NHR.sup.20c, carbocyclyl optionally substituted with 1-5
R.sup.21; and heterocarbocyclyl optionally substituted with 1-5
R.sup.21; [0147] R.sup.20a is C.sub.1-C.sub.20 alkyl,
C.sub.2-C.sub.20 alkenyl, or C.sub.2-C.sub.20 alkynyl; wherein said
alkyl, alkenyl, or alkynyl is optionally substituted by one or more
halo, C.sub.1-C.sub.4 alkyl, aryl, heteroaryl or --NHR.sup.20b;
[0148] R.sup.20b is an amino protecting group; [0149] R.sup.20c is
carbocyclyl optionally substituted with 1-5 R.sup.22; or
heterocarbocyclyl optionally substituted with 1-5 R.sup.22; [0150]
R.sup.21 is selected from the group consisting of: [0151]
C.sub.1-C.sub.20 alkyl, C.sub.2-C.sub.20 alkenyl, C.sub.2-C.sub.20
alkynyl, C.sub.1-C.sub.20 alkoxy, C.sub.1-C.sub.20 thialkoxy, --OH,
--CN, halo, haloalkyl, --NH.sub.2, --NH(alkyl), --N(alkyl).sub.2,
--NHC(.dbd.O)O-alkyl, --NHC(.dbd.O)alkyl, --C(.dbd.O)O-alkyl,
--C(.dbd.O)alkyl, --S(.dbd.O)-alkyl, --S(.dbd.O).sub.2-alkyl,
--S(.dbd.O)-aryl, --S(.dbd.O).sub.2-aryl, carbocyclyl optionally
substituted with 1-5 R.sup.22; and heterocarbocyclyl optionally
substituted with 1-5 R.sup.22; [0152] R.sup.22 is selected from the
group consisting of: [0153] C.sub.1-C.sub.10 alkyl,
C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, phenyl, halo,
haloalkyl, alkoxy, thialkoxy, amino, alkylamino, dialkylamino,
carboxyl, alkyl-OC(.dbd.O)--, alkyl-C(.dbd.O)--, aryl-OC(.dbd.O)--,
alkyl-OC(.dbd.O)NH--, aryl-OC(.dbd.O)NH--, alkyl-C(.dbd.O)NH--,
alkyl-C(.dbd.O)O--, (alkyl-O).sub.r-alkyl,
HO-(alkyl-O).sub.r-alkyl-, --OH, --SH, --CN, --N.sub.3, --CNO,
--CNS, alkyl-S(.dbd.O)--, alkyl-S(.dbd.O).sub.2--,
H.sub.2NS(.dbd.O)--, and H.sub.2NS(.dbd.O).sub.2--; [0154] R.sup.23
is selected from the group consisting of: [0155] C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, F, Cl, Br,
I, haloalkyl, --NH.sub.2, --NHR.sup.23a, --N(R.sup.23a).sub.2,
--N.sub.3, --NO.sub.2, --CN, --CNO, --CNS, --C(.dbd.)OR.sup.23a,
--C(.dbd.O)R.sup.23a, --OC(.dbd.O)R.sup.23a,
--N(R.sup.23a)C(.dbd.O)R.sup.23a, --C(.dbd.O)N(R.sup.23a).sub.2,
ureido, --OR.sup.23a, --SR.sup.23a,
--S(.dbd.O).sub.2--(C.sub.1-C.sub.6 alkyl), --S(.dbd.O).sub.2-aryl,
and --S(.dbd.O).sub.2--N(R.sup.23a).sub.2; [0156] R.sup.23a is H or
C.sub.1-C.sub.6 alkyl; [0157] alternatively, two R.sup.23a may be
combined, together with the N atom to which they are attached, to
form a 5 to 7 membered heterocyclic group; and [0158] r is 2, 3, 4,
5, 6, 7, 8, 9, or 10; and [0159] with the proviso that when Q is a
1,1,2,2-tetramethylethanediol boronic ester, then X is not
aralkyloxycarbonyl; [0160] with the proviso that when Q is a
1,1,2,2-tetramethylethanediol boronic ester, and R.sup.1 is
cycloalkyl, then R.sup.2 is not --CH.sub.2CONH.sub.2; and [0161]
with the proviso that when X is R.sup.AC(.dbd.O)--, R.sup.A is a
C.sub.4-C.sub.15 straight-chained alkyl substituted with R.sup.20,
and R.sup.20 is --CN, --CO.sub.2H, --C(.dbd.O)O--R.sup.20a,
--NHS(.dbd.O).sub.2R.sup.20a, --NHC(.dbd.O)R.sup.20a,
--NHR.sup.20b, or phthalimido; then R.sup.2 is not
--(CH.sub.2).sub.aCH.sub.2NHC(.dbd.NR.sup.4)NH--Y, wherein Y is H,
--CN, --NO.sub.2, or a guanidino protecting group.
[0162] In some embodiments, R.sup.1 is 2-propyl; R.sup.2 is H,
--(CH.sub.2).sub.aCH.sub.2NHC(.dbd.NR.sup.4)NH--Y,
--(CH.sub.2).sub.bCH.sub.2CONR.sup.5R.sup.6,
--(CH.sub.2).sub.cCH.sub.2N(R.sup.4)CONH.sub.2,
--(CH.sub.2).sub.dCH(R.sup.7)NR.sup.9R.sup.10, or
--(CH.sub.2).sub.eCH(R.sup.7)ZR.sup.8; Q is --B(OH).sub.2 or
pinanediol boronic ester; X is R.sup.AC(.dbd.O)--; and R.sup.A is
C.sub.4-C.sub.16 alkyl; aryl optionally substituted with 1-3
R.sup.21; or heterocarbocyclyl group optionally substituted with
1-3 R.sup.21.
[0163] In some embodiments, the present invention provides
compounds of Formula (I)
##STR00012##
or pharmaceutically acceptable salt, stereoisomeric or tautomeric
form thereof, wherein: [0164] R.sup.1 is C.sub.1-C.sub.8 alkyl;
[0165] R.sup.2 is --(CH.sub.2).sub.aCH.sub.2NHC(.dbd.NH)NH--Y,
--(CH.sub.2).sub.cCH.sub.2NHCONH.sub.2,
--(CH.sub.2).sub.dCH(R.sup.7)NR.sup.9R.sup.10, or
--(CH.sub.2).sub.eCH(R.sup.7)ZR.sup.8; [0166] a is 1, 2, 3, 4, or
5; [0167] c is 1, 2, 3, 4, or 5; [0168] d is 0, 1, or 2; [0169] e
is 0, 1, or 2; [0170] R.sup.7 is H or methyl; [0171] R.sup.8 is H,
C.sub.1-C.sub.10 alkyl, --S(.dbd.O).sub.2-alkyl,
--S(.dbd.O).sub.2-aryl, --S(.dbd.O).sub.2--NH.sub.2, --SO.sub.3H,
or a protecting group; [0172] Y is --H, --CN, --NO.sub.2,
--S(.dbd.O).sub.2R.sup.11, or a guanidino protecting group; [0173]
R.sup.9 is H, C.sub.1-C.sub.10 alkyl, carbocyclyl, or
heterocarbocyclyl; [0174] R.sup.10 is H, C.sub.1-C.sub.10 alkyl,
carbocyclyl, heterocarbocyclyl, C.sub.1-C.sub.10 alkyl-C(.dbd.O)--,
carbocyclyl-C(.dbd.O)--, heterocarbocyclyl-C(.dbd.O)--,
carbocyclylalkyl-C(.dbd.O)--, heterocarbocyclylalkyl-C(.dbd.O)--,
C.sub.1-C.sub.10 alkyl-S(.dbd.O).sub.2--,
carbocyclyl-S(.dbd.O).sub.2--, heterocarbocyclyl-S(.dbd.O).sub.2--,
carbocyclylalkyl-S(.dbd.O).sub.2--,
heterocarbocyclylalkyl-S(.dbd.O).sub.2--, C.sub.1-C.sub.10
alkyl-NHC(.dbd.O)--, carbocyclyl-NHC(.dbd.O)--,
heterocarbocyclyl-NHC(.dbd.O)--, carbocyclylalkyl-NHC(.dbd.O)--,
heterocarbocyclylalkyl-NHC(.dbd.O)--, C.sub.1-C.sub.10
alkyl-OC(.dbd.O)--, carbocyclyl-OC(.dbd.O)--,
heterocarbocyclyl-OC(.dbd.O)--, carbocyclylalkyl-OC(.dbd.O)--,
heterocarbocyclylalkyl-OC(.dbd.O)--, or an amino protecting group;
wherein R.sup.10 is optionally substituted with 1, 2 or 3 R.sup.23;
[0175] alternatively, R.sup.9 and R.sup.10 together with the N atom
to which they are attached form a heterocarbocyclyl group; [0176]
R.sup.11 is C.sub.1-C.sub.6 alkyl, aryl, or NR.sup.12R.sup.13;
[0177] R.sup.12 and R.sup.13 are, independently, H,
C.sub.1-C.sub.10 alkyl, carbocyclyl, heterocarbocyclyl, or an amino
protecting group; [0178] alternatively, R.sup.12 and R.sup.13
together with the N atom to which they are attached form a
heterocarbocyclyl group; [0179] Z is O or S; [0180] Q is
--B(OH).sub.2, --B(OR.sup.14).sub.2, or a cyclic boronic ester
wherein said cyclic boronic ester contains from 6 to 20 carbon
atoms and contains at least one cycloalkyl moiety; [0181] R.sup.14
is H, C.sub.1-C.sub.4 alkyl, or cycloalkyl; [0182] X is
R.sup.AC(.dbd.O)--, R.sup.ANHC(.dbd.O)--, R.sup.AS(.dbd.O).sub.2--,
R.sup.AC(.dbd.O)--, R.sup.ASC(.dbd.O)--, or R.sup.A; [0183] R.sup.A
is C.sub.1-C.sub.20 alkyl optionally substituted with R.sup.20;
C.sub.2-C.sub.20 alkenyl optionally substituted with R.sup.20;
C.sub.2-C.sub.20 alkynyl optionally substituted with R.sup.20;
carbocyclyl optionally substituted with 1-5 R.sup.21; or
heterocarbocyclyl optionally substituted with 1-5 R.sup.21; [0184]
R.sup.20 is selected from the group consisting of: [0185] --CN,
halo, haloalkyl-, C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl,
C.sub.2-C.sub.4 alkynyl, --CO.sub.2H, --C(.dbd.O)CO.sub.2H,
--C(.dbd.O)NH.sub.2, --C(.dbd.O)H, --S(.dbd.O)NH.sub.2,
--S(.dbd.O).sub.2NH.sub.2, --OH, --SH, --NH.sub.2, --NH(alkyl),
--N(alkyl).sub.2, --NHC(.dbd.O)NH.sub.2, --NHC(.dbd.O)R.sup.20a,
--NHC(.dbd.O)OR.sup.20a, --OR.sup.20a, --SR.sup.20a,
--S(.dbd.O)R.sup.20a, --S(.dbd.O).sub.2R.sup.20a,
--S(.dbd.O).sub.2--NHR.sup.20a, --SC(.dbd.O)R.sup.20a,
--C(.dbd.O)R.sup.20a, --C(.dbd.O)NHR.sup.20a,
--C(.dbd.O)O--R.sup.20a, --NHS(.dbd.O).sub.2R.sup.20a,
--NHR.sup.20b, phthalimido, --(O-alkyl).sub.r, --O-alkyl-OH,
--(O-alkyl).sub.r-OH, --OR.sup.20c, --SR.sup.20c,
--O-alkyl-R.sup.20c, --S-alkyl-R.sup.20c, --S(.dbd.O)--R.sup.20c,
--S(.dbd.O).sub.2--R.sup.20c, --S(.dbd.O).sub.2--NHR.sup.20c,
--SC(.dbd.O)R.sup.20c, --C(.dbd.O)R.sup.20c, --C(.dbd.O)OR.sup.20c,
--C(.dbd.O)NHR.sup.20c, carbocyclyl optionally substituted with 1-5
R.sup.21; and heterocarbocyclyl optionally substituted with 1-5
R.sup.21; [0186] R.sup.20a is C.sub.1-C.sub.20 alkyl,
C.sub.2-C.sub.20 alkenyl, or C.sub.2-C.sub.20 alkynyl; wherein said
alkyl, alkenyl, or alkynyl is optionally substituted by one or more
halo, C.sub.1-C.sub.4 alkyl, aryl, heteroaryl or --NHR.sup.20b;
[0187] R.sup.20b is an amino protecting group; [0188] R.sup.20c is
carbocyclyl optionally substituted with 1-5 R.sup.22; or
heterocarbocyclyl optionally substituted with 1-5 R.sup.22; [0189]
R.sup.21 is selected from the group consisting of: [0190]
C.sub.1-C.sub.20 alkyl, C.sub.2-C.sub.20 alkenyl, C.sub.2-C.sub.20
alkynyl, C.sub.1-C.sub.20 alkoxy, C.sub.1-C.sub.20 thialkoxy, --OH,
--CN, halo, haloalkyl, --NH.sub.2, --NH(alkyl), --N(alkyl).sub.2,
--NHC(.dbd.O)O-alkyl, --NHC(.dbd.O)alkyl, --C(.dbd.O)O-alkyl,
--C(.dbd.O)alkyl, --S(.dbd.O)-alkyl, --S(.dbd.O).sub.2-alkyl,
--S(.dbd.O)-aryl, --S(.dbd.O).sub.2-aryl, carbocyclyl optionally
substituted with 1-5 R.sup.22, and heterocarbocyclyl optionally
substituted with 1-5 R.sup.22; [0191] R.sup.22 is selected from the
group consisting of: [0192] C.sub.1-C.sub.10 alkyl,
C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, phenyl, halo,
haloalkyl, alkoxy, thialkoxy, amino, alkylamino, dialkylamino,
carboxyl, alkyl-OC(.dbd.O)--, alkyl-C(.dbd.O)--, aryl-OC(.dbd.O)--,
alkyl-OC(.dbd.O)NH--, aryl-OC(.dbd.O)NH--, alkyl-C(.dbd.O)NH--,
alkyl-C(.dbd.O)O--, (alkyl-O).sub.r-alkyl,
HO-(alkyl-O).sub.r-alkyl-, --OH, --SH, --CN, --N.sub.3, --CNO,
--CNS, alkyl-S(.dbd.O)--, alkyl-S(.dbd.O).sub.2--,
H.sub.2NS(.dbd.O)--, and H.sub.2NS(.dbd.O).sub.2--; [0193] R.sup.23
is selected from the group consisting of: [0194] C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, F, Cl, Br,
I, haloalkyl, --NH.sub.2, --NHR.sup.23a, --N(R.sup.23a).sub.2,
--N.sub.3, --NO.sub.2, --CN, --CNO, --CNS, --C(.dbd.O)OR.sup.23a,
--C(.dbd.O)R.sup.23a, --OC(.dbd.O)R.sup.23a,
--N(R.sup.23a)C(.dbd.O)R.sup.23a, --C(.dbd.O)N(R.sup.23a).sub.2,
ureido, --OR.sup.23a, --SR.sup.23a,
--S(.dbd.O).sub.2--(C.sub.1-C.sub.6 alkyl), --S(.dbd.O).sub.2-aryl,
and --S(.dbd.O).sub.2--N(R.sup.23a).sub.2; [0195] R.sup.23a is H or
C.sub.1-C.sub.6 alkyl; [0196] alternatively, two R.sup.23a may be
combined, together with the N atom to which they are attached, to
form a 5 to 7 membered heterocyclic group; and [0197] r is 2, 3, 4,
5, 6, 7, 8, 9, or 10; [0198] with the proviso that when X is
R.sup.AC(.dbd.O)--, R.sup.A is a C.sub.4-C.sub.15 straight-chained
alkyl substituted with R.sup.20, and R.sup.20 is --CN, --CO.sub.2H,
--C(.dbd.O)0--R.sup.20a, --NHS(.dbd.O).sub.2R.sup.20a,
--NHC(.dbd.O)R.sup.20a, --NHR.sup.20b, or phthalimido; then R.sup.2
is not --(CH.sub.2).sub.aCH.sub.2NHC(.dbd.NR.sup.4)NH--Y, wherein Y
is H, --CN, --NO.sub.2, or a guanidino protecting group.
[0199] In further embodiments, the present invention provides
compounds of Formula (I)
##STR00013##
or pharmaceutically acceptable salt, stereoisomeric or tautomeric
form thereof, wherein: [0200] R.sup.1 is C.sub.1-C.sub.4 alkyl;
[0201] R.sup.2 is --(CH.sub.2).sub.aCH.sub.2NHC(.dbd.NH)NH--Y,
--(CH.sub.2).sub.cCH.sub.2NHCONH.sub.2, or
--(CH.sub.2).sub.dCH(R.sup.7)NR.sup.9R.sup.10; [0202] a is 1, 2, or
3; [0203] c is 1, 2, or 3; [0204] d is 0 or 1; [0205] R.sup.7 is H
or methyl; [0206] R.sup.9 is H or C.sub.1-C.sub.10 alkyl; [0207]
R.sup.10 is H, C.sub.1-C.sub.10 alkyl, or an amino protecting
group; [0208] Y is H, CN, or NO.sub.2; [0209] Q is --B(OH).sub.2,
pinanediol boronic ester, bicyclohexyl-1,1'-diol boronic ester, or
1,2-dicyclohexyl-ethane-1,2-diol boronic ester; [0210] X is
R.sup.AC(.dbd.O)--, R.sup.ANHC(.dbd.O)--, R.sup.AS(.dbd.O).sub.2--,
R.sup.AC(.dbd.O)--, R.sup.ASC(.dbd.O)--, or R.sup.A; [0211] R.sup.A
is C.sub.1-C.sub.20 alkyl optionally substituted with R.sup.20;
C.sub.2-C.sub.20 alkenyl optionally substituted with R.sup.20;
C.sub.2-C.sub.20 alkynyl optionally substituted with R.sup.20;
carbocyclyl optionally substituted with 1-5 R.sup.21; or
heterocarbocyclyl optionally substituted with 1-5 R.sup.21; [0212]
R.sup.20 is selected from the group consisting of: [0213] --CN,
halo, haloalkyl-, C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl,
C.sub.2-C.sub.4 alkynyl, --CO.sub.2H, --C(.dbd.O)CO.sub.2H,
--C(.dbd.O)NH.sub.2, --C(.dbd.O)H, --S(.dbd.O)NH.sub.2,
--S(.dbd.O).sub.2NH.sub.2, --OH, --SH, --NH.sub.2, --NH(alkyl),
--N(alkyl).sub.2, --NHC(.dbd.O)NH.sub.2, --NHC(.dbd.O)R.sup.20a,
--NHC(.dbd.O)OR.sup.20a, --OR.sup.20a, --SR.sup.20a,
--S(.dbd.O)R.sup.20a, --S(.dbd.O).sub.2R.sup.20a,
--S(.dbd.O).sub.2--NHR.sup.20a, --SC(.dbd.O)R.sup.20a,
--C(.dbd.O)R.sup.20a, --C(.dbd.O)NHR.sup.20a,
--C(.dbd.O)O--R.sup.20a, --NHS(.dbd.O).sub.2R.sup.20a,
--NHR.sup.20b, phthalimido, --(O-alkyl).sub.r, --O-alkyl-OH,
--(O-alkyl).sub.r-OH, --OR.sup.20c, --SR.sup.20c,
--O-alkyl-R.sup.20c, --S-alkyl-R.sup.20c, --S(.dbd.O)--R.sup.20c,
--S(.dbd.O).sub.2--R.sup.20c, --S(.dbd.O).sub.2--NHR.sup.20c,
--SC(.dbd.O)R.sup.20c, --C(.dbd.O)R.sup.20c, --C(.dbd.O)OR.sup.20c,
--C(.dbd.O)NHR.sup.20c, carbocyclyl optionally substituted with 1-5
R.sup.21; and heterocarbocyclyl optionally substituted with 1-5
R.sup.21; [0214] R.sup.20a is C.sub.1-C.sub.20 alkyl,
C.sub.2-C.sub.20 alkenyl, or C.sub.2-C.sub.20 alkynyl; wherein said
alkyl, alkenyl, or alkynyl is optionally substituted by one or more
halo, C.sub.1-C.sub.4 alkyl, aryl, heteroaryl or --NHR.sup.20b;
[0215] R.sup.20b is an amino protecting group; [0216] R.sup.20c is
carbocyclyl optionally substituted with 1-5 R.sup.22; or
heterocarbocyclyl optionally substituted with 1-5 R.sup.22; [0217]
R.sup.21 is selected from the group consisting of: C.sub.1-C.sub.20
alkyl, C.sub.2-C.sub.20 alkenyl, C.sub.2-C.sub.20 alkynyl,
C.sub.1-C.sub.20 alkoxy, C.sub.1-C.sub.20 thialkoxy, --OH--CN,
halo, haloalkyl, --NH.sub.2, --NH(alkyl), --N(alkyl).sub.2,
--NHC(.dbd.O)O-alkyl, --NHC(.dbd.O)alkyl, --C(.dbd.O)O-alkyl,
--C(.dbd.O)alkyl, --S(.dbd.O)-alkyl, --S(.dbd.O).sub.2-alkyl,
--S(.dbd.O)-aryl, --S(.dbd.O).sub.2-aryl, carbocyclyl optionally
substituted with 1-5 R.sup.22, and heterocarbocyclyl optionally
substituted with 1-5 R.sup.22; [0218] R.sup.22 is selected from the
group consisting of: [0219] C.sub.1-C.sub.10 alkyl,
C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, phenyl, halo,
haloalkyl, alkoxy, thialkoxy, amino, alkylamino, dialkylamino,
carboxyl, alkyl-OC(.dbd.O)--, alkyl-C(.dbd.O)--, aryl-OC(.dbd.O)--,
alkyl-OC(.dbd.O)NH--, aryl-OC(.dbd.O)NH--, alkyl-C(.dbd.O)NH--,
alkyl-C(.dbd.O)O--, (alkyl-O).sub.r-alkyl,
HO-(alkyl-O).sub.r-alkyl-, --OH, --SH, --CN, --N.sub.3, --CNO,
--CNS, alkyl-S(.dbd.O)--, alkyl-S(.dbd.O).sub.2--,
H.sub.2NS(.dbd.O)--, and H.sub.2NS(.dbd.O).sub.2--; and [0220] r is
2, 3, 4, or 5; [0221] with the proviso that when X is
R.sup.AC(.dbd.O)--, R.sup.A is a C.sub.4-C.sub.15 straight-chained
alkyl substituted with R.sup.20, and R.sup.20 is --CN, --CO.sub.2H,
--C(.dbd.O)O--R.sup.20a, --NHS(.dbd.O).sub.2R.sup.20a,
--NHC(.dbd.O)R.sup.20a, --NHR.sup.20b, or phthalimido; then R.sup.2
is not --(CH.sub.2).sub.aCH.sub.2NHC(.dbd.NR.sup.4)NH--Y, wherein Y
is H, --CN, or --NO.sub.2.
[0222] In yet further embodiments, the present invention provides
compound of Formula (I) or pharmaceutically acceptable salt,
stereoisomeric or tautomeric form thereof, wherein: [0223] R.sup.1
is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, or C.sub.3-C.sub.2 cycloalkyl; [0224] R.sup.2 is
--CH.sub.2NH.sub.2 or --CH.sub.2NR.sup.9R.sup.10; [0225] R.sup.9 is
H or C.sub.1-C.sub.10 alkyl; [0226] R.sup.10 is H, C.sub.1-C.sub.10
alkyl, carbocyclyl, heterocarbocyclyl, C.sub.1-C.sub.10
alkyl-C(.dbd.O)--, carbocyclyl-C(.dbd.O)--,
heterocarbocyclyl-C(.dbd.O)--, carbocyclylalkyl-C(.dbd.O)--,
heterocarbocyclylalkyl-C(.dbd.O)--, C.sub.1-C.sub.10
alkyl-S(.dbd.O).sub.2--, carbocyclyl-S(.dbd.O).sub.2--,
heterocarbocyclyl-S(.dbd.O).sub.2--,
carbocyclylalkyl-S(.dbd.O).sub.2--,
heterocarbocyclylalkyl-S(.dbd.O).sub.2--, C.sub.1-C.sub.10
alkyl-NHC(.dbd.O)--, carbocyclyl-NHC(.dbd.O)--,
heterocarbocyclyl-NHC(.dbd.O)--, carbocyclylalkyl-NHC(.dbd.O)--,
heterocarbocyclylalkyl-NHC(.dbd.O)--, C.sub.1-C.sub.10
alkyl-OC(.dbd.O)--, carbocyclyl-OC(.dbd.O)--,
heterocarbocyclyl-OC(.dbd.O)--, carbocyclylalkyl-OC(.dbd.O)--,
heterocarbocyclylalkyl-OC(.dbd.O)--, or an amino protecting group;
wherein R.sup.10 is optionally substituted with 1, 2 or 3,
R.sup.23; [0227] alternatively, R.sup.9 and R.sup.10 together with
the N atom to which they are attached form a heterocarbocyclyl
group; [0228] Q is --B(OH).sub.2, --B(OR.sup.14).sub.2, or a cyclic
boronic ester wherein said cyclic boronic ester contains from 2 to
20 carbon atoms, and, optionally, a heteroatom which can be N, S,
or O; [0229] R.sup.14 is H, C.sub.1-C.sub.4 alkyl, cycloalkyl,
cycloalkylalkyl, aryl, or aralkyl; [0230] X is R.sup.AC(.dbd.O)--,
R.sup.ANHC(.dbd.O)--, R.sup.AS(.dbd.O).sub.2--, R.sup.AC(.dbd.O)--,
R.sup.ASC(.dbd.O)--, or R.sup.A; [0231] R.sup.A is C.sub.1-C.sub.20
alkyl optionally substituted with R.sup.20; C.sub.2-C.sub.20
alkenyl optionally substituted with R.sup.20; C.sub.2-C.sub.20
alkynyl optionally substituted with R.sup.20; carbocyclyl
optionally substituted with 1-5 R.sup.21; or heterocarbocyclyl
optionally substituted with 1-5 R.sup.21; [0232] R.sup.20 is
selected from the group consisting of: [0233] --CN, halo,
haloalkyl-, C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl,
C.sub.2-C.sub.4 alkynyl, --CO.sub.2H, --C(.dbd.O)CO.sub.2H,
--C(.dbd.O)NH.sub.2, --C(.dbd.O)H, --S(.dbd.O)NH.sub.2,
--S(.dbd.O).sub.2NH.sub.2, --OH, --SH, --NH.sub.2, --NH(alkyl),
--N(alkyl).sub.2, --NHC(.dbd.O)NH.sub.2, --NHC(.dbd.O)R.sup.20a,
--SC(.dbd.O)R.sup.20a, --C(.dbd.O)R.sup.20a,
--C(.dbd.O)NHR.sup.20a, --S(.dbd.O).sub.2--NHR.sup.20a,
--SC(.dbd.O).sup.20a, --C(.dbd.O)R.sup.20a, --C(.dbd.O)NHR.sup.20a,
--C(.dbd.O)O--R.sup.20a, --NHS(.dbd.O).sub.2R.sup.20a,
--NHR.sup.20b, phthalimido, --(O-alkyl).sub.r, --O-alkyl-OH,
--(O-alkyl).sub.r-OH, --OR.sup.20c, --SR.sup.20c,
--O-alkyl-R.sup.20c, --S-alkyl-R.sup.20c, --S(.dbd.O)--R.sup.20c,
--S(.dbd.O).sub.2--R.sup.20c, --S(.dbd.O).sub.2--NHR.sup.20c,
--SC(.dbd.O)R.sup.20c, --C(.dbd.O)R.sup.20c,
--C(.dbd.O)NHR.sup.20c, carbocyclyl optionally substituted with 1-5
R.sup.21; and heterocarbocyclyl optionally substituted with 1-5
R.sup.21; [0234] R.sup.20a is C.sub.1-C.sub.20 alkyl,
C.sub.2-C.sub.20 alkenyl, or C.sub.2-C.sub.20 alkynyl; wherein said
alkyl, alkenyl, or alkynyl is optionally substituted by one or more
halo, C.sub.1-C.sub.4 alkyl, aryl, heteroaryl or --NHR.sup.20b;
[0235] R.sup.20b is an amino protecting group; [0236] R.sup.20c is
carbocyclyl optionally substituted with 1-5 R.sup.22; or
heterocarbocyclyl optionally substituted with 1-5 R.sup.22; [0237]
R.sup.21 is selected from the group consisting of: [0238]
C.sub.1-C.sub.20 alkyl, C.sub.2-C.sub.20 alkenyl, C.sub.2-C.sub.20
alkynyl, C.sub.1-C.sub.20 alkoxy, C.sub.1-C.sub.20 thialkoxy,
--OH--CN, halo, haloalkyl, --NH.sub.2, --NH(alkyl),
--N(alkyl).sub.2, --NHC(.dbd.O)O-alkyl, --NHC(.dbd.O)alkyl,
--C(.dbd.O)O-alkyl, --C(.dbd.O)alkyl, --S(.dbd.O)-alkyl,
--S(.dbd.O).sub.2-alkyl, --S(.dbd.O)-aryl, --S(.dbd.O).sub.2-aryl,
carbocyclyl optionally substituted with 1-5 R.sup.22, and
heterocarbocyclyl optionally substituted with 1-5 R.sup.22; [0239]
R.sup.22 is selected from the group consisting of: [0240]
C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10
alkynyl, phenyl, halo, haloalkyl, alkoxy, thialkoxy, amino,
alkylamino, dialkylamino, carboxyl, alkyl-OC(.dbd.O)--,
alkyl-C(.dbd.O)--, aryl-OC(.dbd.O)--, alkyl-OC(.dbd.O)NH--,
aryl-OC(.dbd.O)NH--, alkyl-C(.dbd.O)NH--, alkyl-C(.dbd.O)O--,
(alkyl-O).sub.r-alkyl, HO-(alkyl-O).sub.r-alkyl-, --OH, --SH, --CN,
--N.sub.3, --CNO, --CNS, alkyl-S(.dbd.O)--,
alkyl-S(.dbd.O).sub.2--, H.sub.2NS(.dbd.O)--, and
H.sub.2NS(.dbd.O).sub.2--; [0241] R.sup.23 is selected from the
group consisting of: [0242] C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, F, Cl, Br, I, haloalkyl,
--NH.sub.2, --NHR.sup.23a, --N(R.sup.23a).sub.2, --N.sub.3,
--NO.sub.2, --CN, --CNO, --CNS, --C(.dbd.O)OR.sup.23a,
--C(.dbd.O)R.sup.23a, --OC(.dbd.O)R.sup.23a,
--N(R.sup.23a)C(.dbd.O)R.sup.23a, --C(.dbd.O)N(R.sup.23a).sub.2,
ureido, --OR.sup.23a, --SR.sup.23a,
--S(.dbd.O).sub.2--(C.sub.1-C.sub.6 alkyl), --S(.dbd.O).sub.2-aryl,
and --S(.dbd.O).sub.2--N(R.sup.23a).sub.2; [0243] R.sup.23a is H or
C.sub.1-C.sub.6 alkyl; [0244] alternatively, two R.sup.23a may be
combined, together with the N atom to which they are attached, to
form a 5 to 7 membered heterocyclic group; and [0245] r is 2, 3, 4,
or 5.
[0246] In yet further embodiments, the present invention provides
compounds of Formula (I) or pharmaceutically acceptable salt,
stereoisomeric or tautomeric form thereof, wherein: [0247] R.sup.1
is C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, or C.sub.3-C.sub.2 cycloalkyl; [0248] R.sup.2 is H; [0249]
Q is --B(OH).sub.2, --B(OR.sup.14).sub.2, or a cyclic boronic ester
wherein said cyclic boronic ester contains from 2 to 20 carbon
atoms, and, optionally, a heteroatom which can be N, S, or O;
[0250] R.sup.14 is H, C.sub.1-C.sub.4 alkyl, cycloalkyl,
cycloalkylalkyl, aryl, or aralkyl; [0251] X is R.sup.AC(.dbd.O)--,
R.sup.ANHC(.dbd.O)--, R.sup.AS(.dbd.O).sub.2--, R.sup.AC(.dbd.O)--,
R.sup.ASC(.dbd.O)--, or R.sup.A; [0252] R.sup.A is C.sub.1-C.sub.20
alkyl optionally substituted with R.sup.20; C.sub.2-C.sub.20
alkenyl optionally substituted with R.sup.20; C.sub.2-C.sub.20
alkynyl optionally substituted with R.sup.20; carbocyclyl
optionally substituted with 1-5 R.sup.22; or heterocarbocyclyl
optionally substituted with 1-5 R.sup.22; [0253] R.sup.20 is
selected from the group consisting of: [0254] --OR.sup.20a,
--SR.sup.20a, --S(.dbd.)R.sup.20a, --S(.dbd.O).sub.2R.sup.20a,
--S(.dbd.O).sub.2--NHR.sup.20a, --SC(.dbd.O)R.sup.20a,
--C(.dbd.O)R.sup.20a, --C(.dbd.O)NHR.sup.20a,
--C(.dbd.O)O--R.sup.20a, phthalimido, --(O-alkyl).sub.r,
--O-alkyl-OH, --(O-alkyl).sub.r-OH, --OR.sup.20c, --SR.sup.20c,
--O-alkyl-R.sup.20c, --S-alkyl-R.sup.20c, --S(.dbd.O)--R.sup.20c,
--S(.dbd.O).sub.2--R.sup.20c, --S(.dbd.O).sub.2--NHR.sup.20c,
--SC(.dbd.O)R.sup.20c, --C(.dbd.O)R.sup.20c, --C(.dbd.O)OR.sup.20c,
--C(.dbd.O)NHR.sup.20c, carbocyclyl optionally substituted with 1-5
R.sup.22; and heterocarbocyclyl optionally substituted with 1-5
R.sup.22; [0255] R.sup.20a is C.sub.1-C.sub.20 alkyl,
C.sub.2-C.sub.20 alkenyl, or C.sub.2-C.sub.20 alkynyl; wherein said
alkyl, alkenyl, or alkynyl is optionally substituted by one or more
halo, C.sub.1-C.sub.4 alkyl, aryl, heteroaryl or --NHR.sup.20b;
[0256] R.sup.20c is carbocyclyl optionally substituted with 1-5
R.sup.22; or heterocarbocyclyl optionally substituted with 1-5
R.sup.22; [0257] R.sup.22 is selected from the group consisting of:
[0258] C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl,
C.sub.2-C.sub.10 alkynyl, phenyl, halo, haloalkyl, alkoxy,
thialkoxy, amino, alkylamino, dialkylamino, carboxyl,
alkyl-OC(.dbd.O)--, alkyl-C(.dbd.O)--, aryl-OC(.dbd.O)--,
alkyl-OC(.dbd.O)NH--, aryl-OC(.dbd.O)NH--, alkyl-C(.dbd.O)NH--,
alkyl-C(.dbd.O)O--, (alkyl-O).sub.r-alkyl,
HO-(alkyl-O).sub.r-alkyl-, --OH, --SH, --CN, --N.sub.3, --CNO,
--CNS, alkyl-S(.dbd.O)--, alkyl-S(.dbd.O).sub.2--,
H.sub.2NS(.dbd.O)--, and H.sub.2NS(.dbd.O).sub.2--; and [0259] r is
2, 3, 4, 5, 6, 7, 8, 9, or 10.
[0260] In yet further embodiments:
X is R.sup.AC(.dbd.O)--, R.sup.ANHC(.dbd.O)--, R.sup.AS(O).sub.2--,
or R.sup.A; R.sup.A is C.sub.1-C.sub.14 alkyl optionally
substituted with R.sup.20; R.sup.20 is --(O-alkyl).sub.r-OH or
--(O-alkyl).sub.r-(O-alkyl); and r is 1, 2, 3, 4, or 5. In further
embodiments, the O-alkyl is methoxy, ethoxy, or propoxy.
[0261] In yet further embodiments, the present invention provides
compounds of Formula (I) or pharmaceutically acceptable salts,
stereoisomeric or tautomeric forms thereof, wherein: [0262] R.sup.1
is 2-propyl; [0263] R.sup.2 is
--CH.sub.2CH.sub.2CH.sub.2NHC(.dbd.NH)NH--NO.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NHC(.dbd.O)NH.sub.2, --CH(CH.sub.3)OH,
--CH.sub.2CONH.sub.2, --CH.sub.2NH.sub.2, or
--CH.sub.2NR.sup.9R.sup.10; [0264] R.sup.9 is H; [0265] R.sup.10 is
methyl-C(.dbd.O)--, ethyl-C(.dbd.O)--, propyl-C(.dbd.O)--,
butyl-C(.dbd.O)--, pentyl-C(.dbd.O)--,
2-(ethoxycarbonyl)ethyl-C(.dbd.O)--, 4-methyl-phenyl-C(.dbd.O)--,
cyclopropyl-C(.dbd.O)--, 4-fluoro-phenyl-C(.dbd.O)--,
4-H.sub.2NSO.sub.2-phenyl-C(.dbd.O)--,
4-H.sub.3CSO.sub.2-phenyl-C(.dbd.O)--, 4-phenyl-phenyl-C(.dbd.O)--,
3,4-dimethoxy-benzyl-C(.dbd.O)--, 3-pyridinyl-C(.dbd.O)--,
2-(hydroxy)-pyridin-3-yl-C(.dbd.O)--,
6-(morpholino)-pyridin-3-yl-C(.dbd.O)--,
2-(pyridin-4-yl)thiazol-4-yl-C(.dbd.O)--, 2-pyrazinyl-C(.dbd.O)--,
2,5-dimethyl-pyrazolyl-C(.dbd.O)--,
N-methyl-2-pyrrolyl-C(.dbd.O)--, 2-pyrrolidinyl-C(.dbd.O)--,
2-thiophenyl-C(.dbd.O)--, 5-isoxazolyl-C(.dbd.O)--,
4-(tetrazol-5-yl)phenyl-C(.dbd.O)--,
(5-tetrazolyl)CH.sub.2--C(.dbd.O)--,
N--H.sub.3CSO.sub.2-piperidinyl-C(.dbd.O)--, butyl-OC(.dbd.O)--,
(benzyl)-OC(.dbd.O)--, (9-fluorenylmethyl)-OC(.dbd.O)--,
pentyl-NHC(.dbd.O)--, propyl-NHC(.dbd.O)--, phenyl-NHC(.dbd.O)--,
4-methyl-phenyl-NHC(.dbd.O)--, methyl-S(.dbd.O).sub.2--,
4-fluoro-phenyl-S(.dbd.O).sub.2--,
4-cyano-phenyl-S(.dbd.O).sub.2--,
1-methyl-imidazol-4-yl-S(.dbd.O).sub.2--,
2-thiophenyl-S(.dbd.O).sub.2--,
(4-methyl-phenyl)-NHC(.dbd.O)NH--S(.dbd.O).sub.2--, and
(4-methyl-phenyl)-S(.dbd.O).sub.2NHC(.dbd.O)--, [0266]
alternatively, R.sup.9 and R.sup.10 together with the N atom to
which they are attached form pyrrolyl or pyrazolyl; [0267] Q is
--B(OH).sub.2, pinanediol boronic ester, bicyclohexyl-1,1'-diol
boronic ester, or 1,2-dicyclohexyl-ethane-1,2-diol boronic ester;
[0268] X is R.sup.AC(.dbd.O)--, R.sup.ANHC(.dbd.O)--,
R.sup.AS(.dbd.O).sub.2--, or R.sup.AC(.dbd.O)--; [0269] R.sup.A is
CH.sub.3--, C.sub.2H.sub.5--, C.sub.3H.sub.7--, C.sub.4H.sub.9--,
C.sub.5H.sub.11--, C.sub.6H.sub.13--, C.sub.7H.sub.15--,
C.sub.8H.sub.17--, C.sub.9H.sub.19--, C.sub.10H.sub.21--,
C.sub.11H.sub.23--, C.sub.12H.sub.25--, C.sub.13H.sub.27--,
adamantyl-, bicycloheptanyl-, C.sub.1-3 alkyl substituted with
R.sup.20; C.sub.2-10 alkenyl substituted with R.sup.20; cyclopropyl
substituted with 0-3 R.sup.21; cyclopentyl substituted with 0-2
R.sup.21; cyclohexyl substituted with 0-2 R.sup.21; phenyl
substituted with 0-3 R.sup.21; naphthyl-substituted with 0-2
R.sup.21; pyrazinyl substituted with 0-1 R.sup.21; quinolinyl
substituted with 0-1 R.sup.21; imidazolyl substituted with 0-1
R.sup.21; tetrahydrofuranyl substituted with 0-1 R.sup.21;
oxothiazolidinyl substituted with 0-1 R.sup.21; benzothiazolyl
substituted with 0-1 R.sup.21; thiazolyl substituted with 0-2
R.sup.21; furanyl substituted with 0-2 R.sup.21; pyrrolidinyl
substituted with 0-1 R.sup.21; piperidinyl substituted with 0-1
R.sup.21; piperazinyl substituted with 0-1 R.sup.21; or pyridinyl
substituted with 0-1 R.sup.21; [0270] R.sup.20 is selected from the
group consisting of: [0271] hydroxy-, methoxy-, ethoxy-, propoxy-,
butoxy-, pentoxy-, hexyloxy-, heptyloxy-, octyloxy-,
methoxyethoxy-, methoxyethoxyethoxy-, methyl-S--, ethyl-S--,
octyl-S--, methyl-C(.dbd.O)S--, (acetylamino)methyl-S--, amino-,
methylamino-, dimethylamino-, methyl-C(.dbd.O)--,
phenyl-C(.dbd.O)--, (H.sub.3CSO.sub.2)phenyl-C(.dbd.O)--,
thiophenyl-C(.dbd.O)--, methyl-OC(.dbd.O)--, ethyl-OC(.dbd.O)--,
butyl-OC(.dbd.O)NH--, methyl-C(.dbd.O)NH--,
methoxyethoxy-methyl-C(.dbd.O)NH--, H.sub.2NC(.dbd.O)--,
methyl-NHC(.dbd.O)--, ethyl-NHC(.dbd.O)--, propyl-NHC(.dbd.O)--,
phenyl-NHC(.dbd.O)--, H.sub.2NC(.dbd.O)NH--,
H.sub.2NS(.dbd.O).sub.2--, octyl-S(.dbd.O).sub.2--,
phenyl-S(.dbd.O).sub.2--, methylphenyl-S(.dbd.O).sub.2--,
thiophenyl-S(.dbd.O).sub.2--, cyclopentyl-, cyclohexyl-,
cycloheptyl-, adamantyl-, bicycloheptanyl-, cyclopentenyl-,
phenyl-, methoxy-phenyl-, methyl-phenyl-, dimethyl-phenyl-,
ethyl-phenyl-, propyl-phenyl-, butyl-phenyl-, fluoro-phenyl-,
difluoro-phenyl-, chloro-phenyl-, bromo-phenyl-, iodo-phenyl-,
dimethylamino-phenyl-, cyclohexyloxy-,
2-isopropyl-5-methyl-cyclohexyloxy-, naphthyl-, methoxynaphthyl-,
naphthyloxy-, phenoxy-, (methyl-phenyl)oxy-, (ethyl-phenyl)oxy-,
(propyl-phenyl)oxy-, (butyl-phenyl)oxy-, (fluoro-phenyl)oxy-,
(chloro-phenyl)oxy-, (bromo-phenyl)oxy-, naphthyl-S--, benzyl-S--,
(methyl-phenyl)methyl-S--, pyrimidinyl-S--, piperidinyl-,
N-methyl-piperidinyl-, N-propyl-piperidinyl-, phthalimido-,
thiophenyl-, methyl-thiophenyl-, imidazolyl-, furnayl-,
tetrazolyl-, oxopyrrolidinyl-, indolyl-, and methyl-indolyl-; and
[0272] R.sup.21 is selected from the group consisting of: [0273]
methyl-, ethyl-, propyl-, butyl-, pentyl-, hexyl-, heptyl-,
ethenyl-, propenyl-, butenyl-, methoxy-, ethoxy-, propoxy-,
phenoxy-, fluoro-, chloro-, bromo-, methyl-C(.dbd.O)--,
butyl-OC(.dbd.O)--, butyl-OC(.dbd.O)NH--, phenyl-, methoxyphenyl-,
fluorophenyl-, chlorophenyl-, bromophenyl-, pyrrolyl-, and
pyridinyl-.
[0274] It is appreciated that certain features of the invention,
which are, for clarity, described in the context of separate
embodiments, may also be provided in combination in a single
embodiment. Conversely, various features of the invention which
are, for brevity, described in the context of a single embodiment,
may also be provided separately or in any suitable
subcombination.
[0275] As used herein, the phrase "boronic acid" refers to a
compound containing a B(OH).sub.2 moiety. In some embodiments,
boronic acid compounds can form oligomeric anhydrides by
dehydration of the boronic moiety. For example, Snyder, et al., J.
Am. Chem. Soc., 1958, 80, 3611 report oligomeric arylboronic acids.
Thus, unless otherwise indicated, "boronic acid", or a chemical
formula containing a --B(OH).sub.2 moiety, is intended to encompass
free boronic acids, oligomeric anhydrides, including but not
limited to, dimers, trimers, tetramers, and mixtures thereof.
[0276] As used herein, "boronic acid anhydride" or "boronic
anhydride" refers to a compound formed by the combination of two or
more molecules of a boronic acid compound of Formula (I), with loss
of one or more water molecules from the boronic acid moieties. When
contacted with water, the boronic acid anhydride compound can be
hydrated to release free boronic acid compound. In some
embodiments, the boronic acid anhydride structure can contain two,
three, four, or more boronic acid units and can have a cyclic or
linear configuration. In some embodiments, the boronic acid
anhydride compound exists substantially in a single oligomeric
form; however, boronic acid anhydrides also encompass mixtures of
different oligomeric boronic acid anhydride as well as free boronic
acids.
[0277] Non-limiting examples of boronic acid anhydrides of the
invention include compounds of Formula (II) and (III) where G is a
moiety of Formula (IV) and t is 0 to 10 or 1, 2, 3, or 4.
##STR00014##
[0278] In some embodiments, at least about 80% of boronic acid
present in a boronic acid anhydride compound exists in a single
oligomeric anhydride form. In further embodiments, at least about
85, about 90, about 95, or about 99% of the boronic acid present in
the boronic acid anhydride exists in a single oligomeric anhydride
form. In some embodiments, the boronic acid anhydride compound
consists essentially of a single oligomeric boronic acid anhydride.
In yet further embodiments, the boronic acid anhydride compound
consists of a single oligomeric boronic acid anhydride. In further
embodiments, the boronic acid anhydride compound contains a
boroxine of Formula (III), wherein t is 1.
[0279] Boronic acid anhydride compounds can be prepared from the
corresponding boronic acid compound by exposure to dehydrating
conditions, including, for example, crystallization,
lyophilization, exposure to heat, and/or exposure to a drying
agent. Some suitable crystallization solvents include ethyl
acetate, dichloromethane, hexanes, ether, benzene, acetonitrile,
ethanol, and mixtures thereof.
[0280] As used herein, the phrase "boronic ester" or "boronic acid
ester" refers to an ester derivative of a boronic acid compound. As
used herein, "cyclic boronic ester" is intended to mean a stable
cyclic boronic moiety of general formula --B(OR)(OR) wherein the
two R substituents are linked together forming a cyclic moiety
(e.g., 3- to 10-membered cycloalkyl group) optionally further
substituted with one or more substituents or fused with (sharing at
least one bond) one or more further carbocyclyl or
heterocarbocyclyl groups. The cyclic boronic ester can contain from
2 to 20 carbon atoms, and optionally, a heteroatom which can be N,
S, or O. Cyclic boronic esters are well known in the art. Examples
of cyclic boronic esters include, but are not limited to,
pinanediol boronic ester, pinacol boronic ester, 1,2-ethanediol
boronic ester, 1,3-propanediol boronic ester, 1,2-propanediol
boronic ester, 2,3-butanediol boronic ester,
1,1,2,2-tetramethylethanediol boronic ester,
1,2-diisopropylethanediol boronic ester, 5,6-decanediol boronic
ester, 1,2-dicyclohexylethanediol boronic ester,
bicyclohexyl-1,1'-diol, diethanolamine boronic ester, and
1,2-diphenyl-1,2-ethanediol boronic ester.
[0281] In some embodiments, the "cyclic boronic ester" has Formula
(II-a):
##STR00015##
wherein:
[0282] D is absent, O, S, NR.sup.16, or CR.sup.15eR.sup.15f;
[0283] R.sup.15a, R.sup.15b, R.sup.15c, R.sup.15d, R.sup.15e,
R.sup.15f are each, independently, H, C.sub.1-C.sub.10 alkyl,
C.sub.3-C.sub.7 cycloalkyl, aryl or heteroaryl, wherein said
C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, aryl or
heteroaryl are each optionally substituted by 1, 2, 3 or 4 halo,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4
haloalkoxy, OH, amino, alkylamino, dialkylamino, aryl, or
heteroaryl;
[0284] or R.sup.15a and R.sup.15b together with the C atoms to
which they are attached form C.sub.3-C.sub.10 cycloalkyl or a 3- to
10-membered heterocycloalkyl group, each optionally substituted by
1, 2, 3 or 4 halo, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 haloalkoxy, OH, amino, alkylamino, dialkylamino,
aryl, or heteroaryl;
[0285] or R.sup.15c and R.sup.15d together with the C atoms to
which they are attached form C.sub.3-C.sub.10 cycloalkyl or a 3- to
10-membered heterocycloalkyl group, each optionally substituted by
1, 2, 3 or 4 halo, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 haloalkoxy, OH, amino, alkylamino, dialkylamino,
aryl, or heteroaryl;
[0286] or R.sup.15b and R.sup.15c together with the C atoms to
which they are attached and the intevening D moiety form aryl,
heteroaryl, C.sub.3-C.sub.10 cycloalkyl or a 3- to 10-membered
heterocycloalkyl group, each optionally substituted by 1, 2, 3 or 4
halo, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 haloalkoxy, OH, amino, alkylamino, dialkylamino,
aryl, or heteroaryl;
[0287] R.sup.16 is H or C.sub.1-C.sub.6 alkyl; and
[0288] p and q are each, independently, 1, 2 or 3.
[0289] In some embodiments, D is absent.
[0290] In some embodiments, D is NR.sup.16.
[0291] In some embodiments, D is NH.
[0292] In some embodiments, D is CH.sub.2.
[0293] In some embodiments, R.sup.15a and R.sup.15b together with
the C atoms to which they are attached form C.sub.3-C.sub.10
cycloalkyl or a 3- to 10-membered heterocycloalkyl group, each
optionally substituted by 1, 2, 3 or 4 halo, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkoxy, OH, amino,
alkylamino, dialkylamino, aryl, or heteroaryl; and R.sup.15c and
R.sup.15d together with the C atoms to which they are attached form
C.sub.3-C.sub.10 cycloalkyl or a 3- to 10-membered heterocycloalkyl
group, each optionally substituted by 1, 2, 3 or 4 halo,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4
haloalkoxy, OH, amino, alkylamino, dialkylamino, aryl, or
heteroaryl.
[0294] In some embodiments, R.sup.15a and R.sup.15b together with
the C atoms to which they are attached form cyclopropyl,
cyclobutyl, cyclopenylyl, cyclohexyl or cycloheptyl; and R.sup.15c
and R.sup.15d together with the C atoms to which they are attached
form cyclopropyl, cyclobutyl, cyclopenylyl, cyclohexyl or
cycloheptyl.
[0295] In some embodiments, D is absent and R.sup.15b and R.sup.15c
together with the C atoms to which they are attached form aryl,
heteroaryl, C.sub.3-C.sub.10 cycloalkyl or a 3- to 10-membered
heterocycloalkyl group, each optionally substituted by 1, 2, 3 or 4
halo, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 haloalkoxy, OH, amino, alkylamino, dialkylamino,
aryl, or heteroaryl.
[0296] In some embodiments, D is absent and R.sup.15b and R.sup.15c
together with the C atoms to which they are attached form
C.sub.3-C.sub.10 cycloalkyl optionally substituted by 1, 2, 3 or 4
halo, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 haloalkoxy, OH, amino, alkylamino, dialkylamino,
aryl, or heteroaryl.
[0297] In some embodiments, D is absent and R.sup.15b and R.sup.15c
together with the C atoms to which they are attached form
C.sub.3-C.sub.10 cycloalkyl optionally substituted by 1, 2, 3 or 4
halo or C.sub.1-C.sub.4 alkyl.
[0298] In some embodiments, D is absent and R.sup.15b and R.sup.15c
together with the C atoms to which they are attached form a
C.sub.7-C.sub.10 bicyclic cycloalkyl group optionally substituted
by 1, 2, 3 or 4 halo or C.sub.1-C.sub.4 alkyl.
[0299] In some embodiments, p and q are each 1.
[0300] In some embodiments, at least one of R.sup.15a, R.sup.15b,
R.sup.15c, R.sup.15d is other than H.
[0301] Further examples of "cyclic boronic esters", as defined
herein, include, boronic esters with the following structures:
##STR00016##
wherein: W is a substituted or unsubstituted C.sub.4-C.sub.10
cycloalkyl ring or a substituted or unsubstituted phenyl ring;
W.sup.1 is, independently at each occurrence, a substituted or
unsubstituted C.sub.3-C.sub.6 cycloalkyl ring. Groups R.sup.15a,
R.sup.15b, R.sup.15c, R.sup.15d, R.sup.15e, R.sup.15f, p and q are,
defined as provided above.
[0302] As used herein, the term "alkyl" or "alkylene" is meant to
refer to a saturated hydrocarbon group which is straight-chained or
branched. Example alkyl groups include methyl (Me), ethyl (Et),
propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl,
isobutyl, s-butyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl,
neopentyl) and the like. An alkyl group can contain from 1 to about
20, from 2 to about 20, from 1 to about 10, from 1 to about 8, from
1 to about 6, from 1 to about 4, or from 1 to about 3 carbon
atoms.
[0303] As used herein, "alkenyl" refers to an alkyl group having
one or more double carbon-carbon bonds. Example alkenyl groups
include ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl,
pentadienyl, hexadienyl, and the like.
[0304] As used herein, "alkynyl" refers to an alkyl group having
one or more triple carbon-carbon bonds. Example alkynyl groups
include ethynyl, propynyl, butynyl, pentynyl, and the like.
[0305] As used herein, "haloalkyl" refers to an alkyl group having
one or more halogen substituents. Example haloalkyl groups include
CF.sub.3, C.sub.2F.sub.5, CHF.sub.2, CCl.sub.3, CHCl.sub.2,
C.sub.2Cl.sub.5, and the like. An alkyl group in which all of the
hydrogen atoms are replaced with halogen atoms can be referred to
as "perhaloalkyl." Examples perhaloalkyl groups include CF.sub.3
and C.sub.2F.sub.5.
[0306] As used herein, "carbocyclyl" groups are saturated (i.e.,
containing no double or triple bonds) or unsaturated (i.e.,
containing one or more double or triple bonds) cyclic hydrocarbon
moieties. Carbocyclyl groups can be mono- or polycyclic. Example
carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, cyclopentenyl, 1,3-cyclopentadienyl,
cyclohexenyl, norbornyl, norpinyl, norcarnyl, adamantyl, phenyl,
and the like. Carbocyclyl groups can be aromatic (e.g., "aryl") or
non-aromatic (e.g., "cycloalkyl"). In some embodiments, carbocyclyl
groups can have from 3 to about 20, 3 to about 10, or 3 to about 7
carbon atoms.
[0307] As used herein, "aryl" refers to aromatic carbocyclyl groups
including monocyclic or polycyclic aromatic hydrocarbons such as,
for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl,
indenyl, and the like. In some embodiments, aryl groups have from 6
to about 18 ring-forming carbon atoms.
[0308] As used herein, "cycloalkyl" refers to non-aromatic
carbocyclyl groups including cyclized alkyl, alkenyl, and alkynyl
groups. Cycloalkyl groups can include bi- or poly-cyclic ring
systems. Example cycloalkyl groups include cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl,
cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl,
adamantyl, and the like. Also included in the definition of
cycloalkyl are moieties that have one or more aromatic rings fused
(i.e., having a bond in common with) to the cycloalkyl ring, for
example, benzo derivatives of cyclopentane (indanyl), cyclohexane
(tetrahydronaphthyl), and the like. In some embodiments, cycloalkyl
groups can have 3, 4, 5, 6, or 7 ring forming carbon atoms. In some
embodiments, cycloalkyl groups can have 0, 1, or 2 double or triple
ring-forming bonds.
[0309] As used herein, "heterocarbocyclyl" groups can be saturated
or unsaturated carbocyclyl groups wherein one or more of the
ring-forming carbon atoms of the carbocyclyl group is replaced with
a heteroatom such as O, S, or N. Heterocarbocyclyl groups can be
aromatic (e.g., "heteroaryl") or non-aromatic (e.g.,
"heterocycloalkyl"). Heterocarbocyclyl groups can correspond to
hydrogenated and partially hydrogenated heteroaryl groups.
Heterocarbocyclyl groups can contain, in addition to at least one
heteroatom, from about 1 to about 20, about 2 to about 10, or about
2 to about 7 carbon atoms and can be attached through a carbon atom
or heteroatom. Examples of heterocarbocyclyl groups include
morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl,
tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole,
benzo-1,4-dioxane, piperidinyl, pyrrolidinyl, is oxazolidinyl,
isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl,
imidazolidinyl, and the like.
[0310] As used herein, "heteroaryl" groups are aromatic
heterocarbocyclyl groups and include monocyclic and polycyclic
aromatic hydrocarbons that have at least one heteroatom ring member
such as sulfur, oxygen, or nitrogen. Heteroaryl groups include,
without limitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,
triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl,
thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuryl, benzothienyl,
benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl
indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl,
carbazolyl, benzimidazolyl, and the like. In some embodiments,
heteroaryl groups can have from 3 to about 20 ring-forming carbon
atoms, and in further embodiments from about 3 to about 12 ring
forming carbon atoms. In some embodiments, heteroaryl groups have 1
to about 4, 1 to about 3, or 1 to 2 heteroatoms.
[0311] As used herein, "heterocycloalkyl" refers to a non-aromatic
heterocarbocyclyl group including cyclized alkyl, alkenyl, and
alkynyl groups where one or more of the ring-forming carbon atoms
is replaced by a heteroatom such as an O, N, or S atom.
Ring-forming carbon and heteroatoms such as S and N can further be
oxidized in a heterocycloalkyl moeity. For example, the
ring-forming carbon or heteroatom can bear one or two oxo or sufido
moieties (e.g., >C.dbd.O, >S.dbd.O, >S(.dbd.O).sub.2,
N.fwdarw.O, etc.). Also included in the definition of
heterocycloalkyl are moieties that have one or more aromatic rings
fused (i.e., having a bond in common with) to the nonaromatic
heterocyclic ring, for example phthalimidyl, naphthalimidyl
pyromellitic diimidyl, phthalanyl, and benzo derivatives of
saturated heterocycles such as indolene and isoindolene groups. In
some embodiments, heterocycloalkyl groups have 3 to about 20
ring-forming atoms. In some embodiments, heterocycloalkyl groups
have 3, 4, 5, 6, or 7 ring-forming atoms. In some embodiments,
heterocycloalkyl groups have 0, 1, or 2 double or triple
ring-forming bonds.
[0312] As used herein, "halo" or "halogen" includes fluoro, chloro,
bromo, and iodo.
[0313] As used herein, "alkoxy" refers to an --O-alkyl group.
Example alkoxy groups include methoxy, ethoxy, propoxy (e.g.,
n-propoxy and isopropoxy), t-butoxy, and the like. In some
embodiments, alkoxy groups have from 1 to 20, 1 to 12, 1 to 8, 1 to
6, 1 to 4 or 1 to 3 carbon atoms.
[0314] As used herein, "alkoxyalkoxy" refers to an
--O-alkyl-O-alkyl group.
[0315] As used herein, "thioalkoxy" refers to an alkoxy group in
which the O atom is replaced by an S atom.
[0316] As used herein, "aryloxy" refers to an --O-aryl group. An
example aryloxy group is phenoxy.
[0317] As used herein, "thioaryloxy" refers to an aryloxy group in
which the O atom is replaced by an S atom.
[0318] As used herein, "aralkyl" refers to an alkyl moiety
substituted by an aryl group. Example aralkyl groups include benzyl
and naphthylmethyl groups. In some embodiments, aralkyl groups have
from 7 to 11 carbon atoms.
[0319] As used herein, "amino" refers to an --NH.sub.2 group.
"Alkylamino" refers to an amino group substituted by an alkyl group
and "dialkylamino" refers to an amino group substituted by two
alkyl groups. On the contrary, "aminoalkyl" refers to an alkyl
group substituted by an amino group.
[0320] As used herein, "carbonyl" refers to >C.dbd.O.
[0321] As used herein, "carboxy" or "carboxyl" refers to
--COOH.
[0322] As used herein, "hydroxy" refers to --OH.
[0323] As used herein, "mercapto" refers to --SH.
[0324] As used herein, "ureido" refers to --NHCONH.sub.2.
[0325] As used herein, "sulfinyl" refers to >SO.
[0326] As used herein, "sulfonyl" refers to >SO.sub.2.
[0327] As used herein, "oxy" refers to --O--.
[0328] The above chemical terms can be combined to refer to
moieties containing a combination of chemical groups. This
combination term is generally read such that a recited term is
understood to be a substituent of a following term. For example,
"alkylcarbonylalkenyl" refers to an alkenyl group substituted by a
carbonyl group which in turn is substituted by an alkyl group. The
following terms can also exemplify such combinations.
[0329] As used herein, "carbocyclylalkyl" refers to an alkyl moiety
substituted by a carbocyclyl group. Example carbocyclylalkyl groups
include "aralkyl" (alkyl substituted by aryl) and "cycloalkylalkyl"
(alkyl substituted by cycloalkyl).
[0330] As used herein, "carbocyclylalkenyl" refers to an alkenyl
moiety substituted by a carbocyclyl group. Example
carbocyclylalkenyl groups include "aralkenyl" (alkenyl substituted
by aryl) and "cycloalkylalkenyl" (alkenyl substituted by
cycloalkyl).
[0331] As used herein, "carbocyclylalkynyl" refers to an alkynyl
moiety substituted by a carbocyclyl group. Example
carbocyclylalkynyl groups include "aralkynyl" (alkynyl substituted
by aryl) and "cycloalkylalkynyl" (alkynyl substituted by
cycloalkyl).
[0332] As used herein, "heterocarbocyclylalkyl" refers to an alkyl
moiety substituted by a heterocarbocyclyl group. Example
heterocarbocyclylalkyl groups include "heteroarylalkyl" (alkyl
substituted by heteroaryl) and "heterocycloalkylalkyl" (alkyl
substituted by heterocycloalkyl).
[0333] As used herein, "heterocarbocyclylalkenyl" refers to an
alkenyl moiety substituted by a heterocarbocyclyl group. Example
heterocarbocyclylalkenyl groups include "heteroarylalkenyl"
(alkenyl substituted by heteroaryl) and "heterocycloalkylalkenyl"
(alkenyl substituted by heterocycloalkyl).
[0334] As used herein, "heterocarbocyclylalkynyl" refers to an
alkynyl moiety substituted by a heterocarbocyclyl group. Example
heterocarbocyclylalkynyl groups include "heteroarylalkynyl"
(alkynyl substituted by heteroaryl) and "heterocycloalkynylalkyl"
(alkynyl substituted by heterocycloalkyl).
[0335] As used herein, the phrase "protecting group" refers to a
chemical functional group that can be selectively appended to and
removed from functionalities, such as hydroxyl groups, amino
groups, and carboxyl groups. Protecting groups are usually
introduced into a chemical compound to render such functionality
inert to chemical reaction conditions to which the compound is
exposed. Any of a variety of protecting groups can be employed with
the present invention. A protecting group of an amino moiety can be
referred to as an "amino protecting group" and a protecting group
of a guanidino moiety can be referred to as a "guanidino protecting
group." Amino and guanidino protecting groups can have the formulas
aryl-SO.sub.2--, alkyl-SO.sub.2--, aryl-C(.dbd.O)--,
aralkyl-C(.dbd.O)--, alkyl-C(.dbd.O)--, aryl-OC(.dbd.O)--,
aralkyl-OC(.dbd.O)--, alkyl-OC(.dbd.O)--, aryl-NHC(.dbd.O)--,
alkyl-NHC(.dbd.O)--, and the like, wherein said alkyl, aryl and
aralkyl groups may be substituted or unsubstituted. Example amino
and guanidino protecting groups can also include t-butyloxycarbonyl
(BOC), fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz),
and a phthalimido group. Other protecting groups include the
following moieties:
##STR00017##
[0336] Further representative protecting groups can be found in T.
W. Green and P. G. M. Wuts, Protective Groups in Organic Synthesis,
3rd. Ed., Wiley & Sons, Inc., New York (1999), which is
incorporated herein by reference in its entirety.
[0337] As used herein, "substituted" indicates that at least one
hydrogen atom of a chemical group is replaced by a non-hydrogen
moiety. Example substituents include F, Cl, Br, I, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkenyl, C.sub.1-C.sub.6, alkynyl,
haloalkyl, NR.sup.ER.sup.F, N.sub.3, NO.sub.2, CN, CNO, CNS,
C(.dbd.O)OR.sup.E, R.sup.ECO, R.sup.EC(.dbd.O)O, R.sup.ECONR.sup.E,
R.sup.ER.sup.FNCO, ureido, OR.sup.E, SR.sup.E, SO.sub.2-alkyl,
SO.sub.2-aryl, and SO.sub.2--NR.sup.ER.sup.F, wherein R.sup.E and
R.sup.F are each, independently, H or C.sub.1-C.sub.6 alkyl.
Alternatively, R.sup.E and R.sup.F may be combined, with the
nitrogen to which they are attached, to form a 5 to 7 membered
heterocyclic ring, for example pyrrolidinyl, piperidinyl,
morpholinyl, piperazinyl, and N-methylpiperazinyl. When a chemical
group herein is "substituted" it may have up to the full valance of
substitution, provided the resulting compound is a stable compound
or stable structure; for example, a methyl group may be substituted
by 1, 2, or 3 substituents, a methylene group may be substituted by
1 or 2 substituents, a phenyl group may be substituted by 1, 2, 3,
4, or 5 substituents, and the like.
[0338] As used herein, "leaving group" refers to any group that can
be replaced by a nucleophile upon nucleophilic substitution.
Example leaving groups include, halo (F, Cl, Br, I), hydroxyl,
alkoxy, mercapto, thioalkoxy, triflate, alkylsulfonyl, substituted
alkylsulfonate, arylsulfonate, substituted arylsulfonate,
heterocyclosulfonate or trichloroacetimidate. Representative
examples include p-(2,4-dinitroanilino)benzenesulfonate,
benzenesulfonate, methylsulfonate, p-methylbenzenesulfonate,
p-bromobenzenesulfonate, trichloroacetimidate, acyloxy,
2,2,2-trifluoroethanesulfonate, imidazolesulfonyl and
2,4,6-trichlorophenyl.
[0339] As used herein "stable compound" or "stable structure"
refers to a compound that is sufficiently robust to survive
isolation to a useful degree of purity from a reaction mixture, and
preferably capable of formulation into an efficacious therapeutic
agent. The present invention is directed only to stable
compounds.
[0340] The compounds described herein can be asymmetric (e.g.,
having one or more stereocenters). All stereoisomers, such as
enantiomers and diastereomers, are intended unless otherwise
indicated. Compounds of the present invention that contain
asymmetrically substituted carbon atoms can be isolated in
optically active or racemic forms. Methods on how to prepare
optically active forms from optically active starting materials are
known in the art, such as by resolution of racemic mixtures or by
stereoselective synthesis. Many geometric isomers of olefins,
C.dbd.N double bonds, and the like can also be present in the
compounds described herein, and all such stable isomers are
contemplated in the present invention. Cis and trans geometric
isomers of the compounds of the present invention are described and
may be isolated as a mixture of isomers or as separated isomeric
forms.
[0341] In addition to the above, the compounds herein described may
have asymmetric centers which result in one enantiomer of a
compound of Formula (I) demonstrating superior biological activity
over the opposite enantiomer. Both of the configurations are
considered part of the invention. For example, the R2 substituent
of a compound of Formula (I) may exist in either an S or R
configuration. An example of a preferred enantiomeric configuration
of the invention is a compound of Formula (I-s):
##STR00018##
but is not intended to be limited to this example. When required,
separation of the racemic material can be achieved by methods known
in the art.
[0342] Compounds of the invention can also include tautomeric
forms, such as keto-enol tautomers. Tautomeric forms can be in
equilibrium or sterically locked into one form by appropriate
substitution.
[0343] Compounds of the invention can also include all isotopes of
atoms occurring in the intermediates or final compounds. Isotopes
include those atoms having the same atomic number but different
mass numbers. For example, isotopes of hydrogen include tritium and
deuterium.
[0344] The phrase "pharmaceutically acceptable" is employed herein
to refer to those compounds, materials, compositions, and/or dosage
forms which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response,
or other problem or complication, commensurate with a reasonable
benefit/risk ratio.
[0345] The present invention also includes pharmaceutically
acceptable salts of the compounds described herein. As used herein,
"pharmaceutically acceptable salts" refers to derivatives of the
disclosed compounds wherein the parent compound is modified by
converting an existing acid or base moiety to its salt form.
Examples of pharmaceutically acceptable salts include, but are not
limited to, mineral or organic acid salts of basic residues such as
amines; alkali or organic salts of acidic residues such as
carboxylic acids; and the like. The pharmaceutically acceptable
salts of the present invention include the conventional non-toxic
salts or the quaternary ammonium salts of the parent compound
formed, for example, from non-toxic inorganic or organic acids. For
example, such conventional non-toxic salts include those derived
from inorganic acids such as hydrochloric, hydrobromic, sulfuric,
sulfamic, phosphoric, nitric and the like; and the salts prepared
from organic acids such as acetic, propionic, succinic, glycolic,
stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic,
hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,
sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,
methanesulfonic, ethane disulfonic, oxalic, isethionic, and the
like. The pharmaceutically acceptable salts of the present
invention can be synthesized from the parent compound which
contains a basic or acidic moiety by conventional chemical methods.
Generally, such salts can be prepared by reacting the free acid or
base forms of these compounds with a stoichiometric amount of the
appropriate base or acid in water or in an organic solvent, or in a
mixture of the two; generally, nonaqueous media like ether, ethyl
acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists
of suitable salts are found in Remington's Pharmaceutical Sciences,
17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and
in the Journal of Pharmaceutical Science, 66, 2 (1977), the
disclosures of each of which are hereby incorporated by
reference.
Synthesis
[0346] Compounds of the invention, including salts and solvates
thereof, can be prepared using known organic synthesis techniques
and can be synthesized according to any of numerous possible
synthetic routes.
[0347] The reactions for preparing compounds of the invention can
be carried out in suitable solvents which can be readily selected
by one of skill in the art of organic synthesis. Suitable solvents
can be substantially nonreactive with the starting materials
(reactants), the intermediates, or products at the temperatures at
which the reactions are carried out, i.e., temperatures which can
range from the solvent's freezing temperature to the solvent's
boiling temperature. A given reaction can be carried out in one
solvent or a mixture of more than one solvent. Depending on the
particular reaction step, suitable solvents for a particular
reaction step can be selected.
[0348] Preparation of Compounds of the Invention can Involve the
Protection and deprotection of various chemical groups. The need
for protection and deprotection, and the selection of appropriate
protecting groups can be readily determined by one skilled in the
art. The chemistry of protecting groups can be found, for example,
in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic
Synthesis, 3rd. Ed., Wiley & Sons, Inc., New York (1999), which
is incorporated herein by reference in its entirety.
[0349] Reactions can be monitored according to any suitable method
known in the art. For example, product formation can be monitored
by spectroscopic means, such as nuclear magnetic resonance
spectroscopy (e.g., .sup.1H or .sup.13C) infrared spectroscopy,
spectrophotometry (e.g., UV-visible), or mass spectrometry, or by
chromatography such as high performance liquid chromatography
(HPLC) or thin layer chromatography.
[0350] Compounds of the invention can be prepared according to
methods for preparing aminoboronic acids, esters thereof, and
related compounds described in the art, such as in U.S. Pat. No.
4,537,773, and in U.S. Pat. No. 5,614,649, each of which is
incorporated herein by reference in its entirety. In some
embodiments, the present compounds can be prepared by the
sequential coupling of three fragment components (F1, F2, and
F3).
F1 Fragment
[0351] Synthesis of compounds of the invention can involve a
boron-containing fragment (F1) having a structure indicated by
Formula (A).
##STR00019##
[0352] The boronic ester moiety of F1 can include, for example, a
diol ester such as is indicated by the loop connecting oxygen atoms
in Formula (A).
[0353] Stereochemistry at the carbon atom alpha to the boron atom
in Formula (A) can be controlled using an asymmetric boronic ester
group in the preparation of F1. For example, pinanediol esters of
boronic acid can facilitate the preparation or stereochemically
pure, or substantially stereochemically pure, F1 fragment. As an
example, the F1 fragment can be prepared by reacting a compound of
Formula (B) (showing a pinanediol boronic ester obtained from
(+)-pinanediol) with a strong base (e.g., lithium diisopropylamide
or lithium dicyclohexylamide) in the presence of dichloromethane or
dibromomethane, followed by addition of a Lewis acid, (e.g.,
ZnCl.sub.2, ZnBr.sub.2, or FeCl.sub.3) to yield a compound of
Formula (C) (where L is halo) having a newly introduced
stereocenter at the carbon alpha to the boron.
##STR00020##
[0354] The compound of Formula (C) can, in turn, be reacted with an
alkali amide (e.g., lithium bis(trimethylsilyl)amide, sodium
bis(trimethylsilyl)amide, and potassium bis(trimethylsilyl)amide)
or other nucleophile that effectively inverts the newly formed
stereocenter (such as by an SN2 type mechanism) and introduces an
amine group (NR.sub.2) in place of the halo group (e.g., chloro),
forming a compound of Formula (D) (where R can be, e.g., alkyl,
Si(alkyl).sub.3, aryl, or aralkyl).
##STR00021##
[0355] The compound of Formula (D) can be further reacted with an
agent capable of converting the NR.sub.2 group to NH.sub.2, or salt
thereof, to form an F1 fragment substantially capable of coupling
with a further fragment through the amine. A suitable agent for
converting the NR.sub.2 group to NH.sub.2 can be a protic acid such
as HCl such as when R is a silyl group (e.g., trimethylsilyl).
[0356] The compound of Formula (B) can also be prepared according
to a two step procedure involving reaction of a trialkoxyborane,
preferably triisopropoxyborane, with (1S,2S,3R,5S)-(+) pinanediol,
to give a mono-alkoxy [(1S,2S,3R,5S)-(+) pinanediol]borane
intermediate wherein two of the alkoxy groups of the trialkoxy
borane have been replaced by (1S,2S,3R,5S)-(+) pinanediol. This
mixed pinanediol alkoxy borane, upon reaction with the appropriate
organometallic derivative, e.g. the Grignard reagent
R.sup.1CH.sub.2MgBr or the alkyl lithium R.sup.1CH.sub.2Li, gives
compound (B) in good yields and purities. The process starting from
triisopropoxyborane to give the intermediate mixed pinanediol
isopropoxy borane (F) and the compounds of formula (B) is depicted
in the following scheme:
##STR00022##
and exemplified in Example A.2, herein.
[0357] Accordingly, the present invention is further directed to
methods of preparing compounds of Formula (II):
##STR00023##
wherein the variable constituents are defined hereinabove, by the
process of a) reacting a diol of Formula (II-b):
##STR00024##
with an appropriate trialkoxyborane of Formula (II-a):
##STR00025##
wherein each R.sup.17 is, independently, C.sub.1-C.sub.10 alkyl or
C.sub.3-C.sub.10 cycloalkyl; for a time and under conditions
suitable for forming a mixed trialkoxyborane intermediate of
Formula (II-c):
##STR00026##
and reacting the intermediate of Formula (II-c) with either i) a
reagent of formula R.sup.1CH.sub.2MX.sup.hal, wherein M is a metal
and X.sup.hal is a halogen atom, or ii) a reagent of formula
R.sup.1CH.sub.2Li, for a time and under conditions suitable for
forming the compound of Formula (II).
[0358] In some embodiments, R.sup.17 is C.sub.1-C.sub.4 alkyl.
[0359] In some embodiments, R.sup.17 is isopropyl.
[0360] In some embodiments, the diol of Formula (II-b) is
pinanediol, pinacol, bicyclohexyl-1,1'-diol, 1,2-ethanediol,
1,3-propanediol, 1,2-propanediol, 2,3-butanediol,
1,1,2,2-tetramethylethanediol, 1,2-diisopropylethanediol,
5,6-decanediol, 1,2-dicyclohexylethanediol, bicyclohexyl-1,1'-diol,
diethanolamine, or 1,2-diphenyl-1,2-ethanediol.
[0361] In some embodiments, the diol of Formula (II-b) is
pinanediol.
[0362] In some embodiments, the Formula R.sup.1CH.sub.2MX.sup.hal
is a Grignard reagent.
[0363] In some embodiments, the Formula R.sup.1CH.sub.2MX.sup.hal
is R.sup.1CH.sub.2MgBr.
[0364] In some embodiments, R.sup.1 is isopropyl.
[0365] In some embodiments, the present invention provides a
process for preparing a compound of Formula (II-i):
##STR00027##
comprising: a) reacting (1S,2S,3R,5S)-(+)-pinanediol with
triisopropoxy borane for a time and under conditions suitable for
forming an intermediate of Formula (II-ii):
##STR00028##
and b) reacting the intermediate of Formula (II-ii) with isobutyl
magnesium bromide for a time and under conditions suitable for
forming the compound of Formula (II-i).
[0366] In some embodiments, the present invention provides a
compound of Formula (II-ii):
##STR00029##
[0367] The reacting steps can be carried out in any suitable
solvent that is non-reactive with the reagents and products and
allows combining of reagents at lowered temperatures (e.g.,
temperatures colder than room temperature). Suitable solvents
include ethers such as dimethoxymethane, tetrahydrofuran,
1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol
dimethyl ether, ethylene glycol diethyl ether, diethylene glycol
dimethyl ether, diethylene glycol diethyl ether, triethylene glycol
dimethyl ether, anisole, or t-butyl methyl ether. In some
embodiments, the ether solvent contains tetrahydrofuran and/or
diethyl ether.
[0368] The reactions of the processes described herein can be
carried out at appropriate temperatures which can be readily
determined by the skilled artisan. Reaction temperatures will
depend on, for example, the melting and boiling points of the
reagents and solvent, if present; the thermodynamics of the
reaction (e.g., vigorously exothermic reactions may need to be
carried out at reduced temperatures); and the kinetics of the
reaction (e.g., a high activation energy barrier may need elevated
temperatures). "Elevated temperature" refers to temperatures above
room temperature (about 22.degree. C.) and "reduced temperature"
refers to temperatures below room temperature.
[0369] In some embodiments, suitable temperatures are reduced
temperatures. The reaction of the trialkoxyborane and diol to
prepare a mixed trialkoxyborane intermediate can be carried out,
for example, at a temperature of about -20 to about 10.degree. C.
In some embodiments, the reaction of the trialkoxyborane and diol
can be carried out at about 0.degree. C. The reaction of the mixed
trialkoxyborane intermediate with the organometallic reagent
R.sup.1CH.sub.2MX.sup.hal or the alkyl lithium reagent
R.sup.1CH.sub.2Li can be carried out, for example, at temperature
from about -100 to about -20.degree. C. In some embodiments, the
reaction of the mixed trialkoxyborane intermediate and
R.sup.1CH.sub.2MX.sup.hal is carried out at about -78.degree.
C.
[0370] The reactions of the processes described herein can be
carried out in air or under an inert atmosphere. Typically,
reactions containing reagents or products that are substantially
reactive with air can be carried out using air-sensitive synthetic
techniques that are well known to the skilled artisan.
B. F2 Fragment
[0371] The mid-section of compounds of the present invention can be
represented by fragment F2 which couples to fragment F1 by peptide
bond formation for form an F2-F1 intermediate. Methods for coupling
compounds through peptide bonds, or amide bonds, are well known in
the art and described, for example, in The Peptides: Analysis,
Synthesis, Biology, Vol. I., eds. Gross, et al., Academic Press,
1979. An example F2 fragment is provided in Formula (E) (Pg is an
amino protecting group, R.sup.2 is defined herein). Additionally,
protection of the amino group of amino acids using Boc or other
amino protecting groups is well known in the art.
##STR00030##
[0372] Compounds of Formula (E) that are amino acids or amino acid
derivatives are available commercially or prepared by routine
methods. For example, aza-serines can be prepared generally by the
Hoffman Rearrangement (Hoffman's Reaction) using, for example,
asparagine where the amide of the asparagine side chain is
converted to an amine (which can be subsequently protected).
Methods for carrying out Hoffman Rearrangements, such as for amino
acids, are known in the art and also provided in the Examples
below. Additionally aza-serines can be prepared as disclosed in
Zhang, et al. J. Org. Chem., 1997, 62, 6918-6920. Boc-cyanoarginine
derivatives can be prepared as disclosed in Wagenaar et al., J.
Org. Chem. 1993, 58, 4331-4338. Synthesis of F2 fragments wherein
R.sup.2 is --CH.sub.2CH.sub.2CH.sub.2NHC(.dbd.NR.sup.4)NH--Y,
--CH.sub.2CONR.sup.5R.sup.6, --CH.sub.2NHCONR.sup.5R.sup.6,
--CH.sub.2NR.sup.9R.sup.10, or --CH(R.sup.7)ZR.sup.8 are further
disclosed herein. F2 fragments can be obtained from commercial
sources or made by methods known to one skilled in the art.
C. F3 Fragments
[0373] A further fragment (F3) can be coupled to the F2 fragment of
the F2-F1 intermediate by any of various means such as by
nucleophilic substitution or addition reactions where, for example,
F2 contains a nucleophile (e.g., amine) and F3 contains an
electrophile (e.g., CO, SO.sub.2, and the like) and optionally a
leaving group (e.g., halo, hydroxy, alkoxy, alkylsulfonyl,
arylsulfonyl, and the like). Example F3 fragments can have the
formula R.sup.XCOX.sup.L, R.sup.XSO.sub.2X.sup.L, R.sup.XNCO, or
R.sup.XHCO, (e.g., R.sup.X can be R.sup.A, R.sup.B, or R.sup.C as
defined herein and X.sup.L can be a leaving group). Coupling of
R.sup.XCOX.sup.L (such as when X.sup.L is OH) to the F2-F1
intermediate can be carried out according to standard procedures
for peptide bond formation to prepare compounds having the formula
F3-F2-F1 where the F3 and F2 fragments are coupled via an amide
bond. In other embodiments, F3 and F2 can be coupled by a
sulfonylamino linkage prepared by reacting R.sup.XSO.sub.2X.sup.L
with the F2-F1 intermediate in which an amino moiety on the F2-F1
intermediate displaces the X.sup.L leaving group of
R.sup.XSO.sub.2X.sup.L. Additionally, reaction of R.sup.XNCO with
an amino moiety of the F2-F1 intermediate can result in a urea
linkage (--HNCONH--), while reaction of R.sup.XHCO with an amino
moiety of the F2-F1 intermediate followed by reduction of the
resulting imine moiety can form an amine linkage. Other coupling
means are known in the art and are also suitable. F3 fragments can
be obtained from commercial sources or made by methods known in the
art.
[0374] Certain compounds of the invention wherein R.sup.2 is
--(CH.sub.2).sub.dCH(R.sup.2)NR.sup.9R.sup.10 can be prepared by
removal of an R.sup.10 amino protecting group to form the
corresponding deprotected compound wherein R.sup.10 is H. This
deprotected compound can be reacted with a reagent having the
formula R.sup.10aX.sup.L, wherein R.sup.10a has the same meaning as
R.sup.10 with the exception of H and X.sup.L is a leaving group
such as halo or a sulfonic acid derivative, or wherein R.sup.10a
and X.sup.L taken together represent, for example, a reactive
alkyl, carbocyclyl or heterocarbocyclyl isocyanate, or an alkyl,
carbocyclyl, heterocarbocyclyl sulphonylisocyanate. For example,
the compound of Example D.26 can be prepared by the deprotection of
the benzyloxycarbonyl group of Example D.16.6 to give Example D.17,
from which the azaserine nitrogen can be subsequently acylated.
[0375] The present invention further provides methods for preparing
azaserine (e.g., where R.sup.2 is --CH.sub.2NH.sub.2) compounds of
Formula I. In general, the azaserine group can be generated by
removal of a benzyloxycarbonyl group
(--C(.dbd.O)OCH.sub.2(C.sub.6H.sub.5)) which is attached to one of
the nitrogens of the azaserine group (e.g., compounds of Formula I
where R.sup.2 is --CH.sub.2NR.sup.9R.sup.10 and R.sup.9 is H and
R.sup.10 is --C(.dbd.O)OCH.sub.2(C.sub.6H.sub.5)). Removal of the
benzyloxycarbonyl group can be carried out by treatment with a
reducing agent, such as a hydrogenation reagent. In some
embodiments, the hydrogenation reagent contains H.sub.2 which is
optionally used in the presence of a metal catalyst (e.g., Pd/C
10%). Hydrogenation can be further carried out in the presence of a
protic acid such as HCl and in a suitable hydrogenation solvent
containing, for example, an alcohol and/or an ether solvent. In
some embodiments, the hydrogenation solvent contains an ether such
as 1,4-dioxane. In further embodiments, the hydrogenation solvent
cotains an alcohol such as methanol. In further embodiments, the
hydrogenation solvent contains a mixture of alcohol and ether. An
example preparation of an azaserine compound according to this
process is provided, for example, in Example D.17. Reaction
parameters including temperature, pressure, atmosphere and the like
are readily determined by one skilled in the art of chemical
synthesis and reaction progress can be monitored by routine methods
including, e.g., NMR.
[0376] Accordingly, the present invention provides a process for
the preparation of compounds of Formula (I):
##STR00031##
wherein: [0377] R.sup.1 is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, or C.sub.3-C.sub.2 cycloalkyl;
[0378] R.sup.2 is --CH.sub.2NH.sub.2; [0379] Q is
--B(OR.sup.14).sub.2, or a cyclic boronic ester wherein said cyclic
boronic ester contains from 2 to 20 carbon atoms, and, optionally,
a heteroatom which can be N, S, or O; [0380] R.sup.14 is
C.sub.1-C.sub.4 alkyl, cycloalkyl, cycloalkylalkyl, aryl, or
aralkyl; [0381] X is R.sup.AC(.dbd.O)--; [0382] R.sup.A is
C.sub.1-C.sub.20 alkyl optionally substituted with R.sup.20;
C.sub.2-C.sub.20 alkenyl optionally substituted with R.sup.20;
C.sub.2-C.sub.20 alkynyl optionally substituted with R.sup.20;
carbocyclyl optionally substituted with 1-5 R.sup.21; or
heterocarbocyclyl optionally substituted with 1-5 R.sup.21; [0383]
R.sup.20 is selected from the group consisting of: [0384] --CN,
halo, haloalkyl-, C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl,
C.sub.2-C.sub.4 alkynyl, --CO.sub.2H, --C(.dbd.O)CO.sub.2H,
--C(.dbd.O)NH.sub.2, --C(.dbd.O)H, --S(.dbd.O)NH.sub.2,
--S(.dbd.O).sub.2NH.sub.2, --OH, --SH, --NH.sub.2, --NH(alkyl),
--N(alkyl).sub.2, --NHC(.dbd.O)NH.sub.2, --NHC(.dbd.O)R.sup.20a,
--NHC(.dbd.O)OR.sup.20a, --OR.sup.20a, --SR.sup.20a,
--S(.dbd.O)R.sup.20a, --S(.dbd.O).sub.2R.sup.20a,
--S(.dbd.O).sub.2--NHR.sup.20a, --SC(.dbd.O)R.sup.20a,
--C(.dbd.O)R.sup.20a, --C(.dbd.O)NHR.sup.20a,
--C(.dbd.O)O--R.sup.20a, --NHS(.dbd.O).sub.2R.sup.20a,
--NHR.sup.20b, phthalimido, --(O-alkyl).sub.r, --O-alkyl-OH,
--(O-alkyl).sub.r-OH, --OR.sup.20c, --SR.sup.20c,
--O-alkyl-R.sup.20c, --S-alkyl-R.sup.20c, --S(.dbd.O)--R.sup.20c,
--S(.dbd.O).sub.2--R.sup.20c, --S(.dbd.O).sub.2--NHR.sup.20c,
--SC(.dbd.O)R.sup.20c, --C(.dbd.O)R.sup.20c, --C(.dbd.O)OR.sup.20c,
C(.dbd.O)NHR.sup.20c, carbocyclyl optionally substituted with 1-5
R.sup.21; and heterocarbocyclyl optionally substituted with 1-5
R.sup.21; [0385] R.sup.20a is C.sub.1-C.sub.20 alkyl,
C.sub.2-C.sub.20 alkenyl, or C.sub.2-C.sub.20 alkynyl; wherein said
alkyl, alkenyl, or alkynyl is optionally substituted by one or more
halo, C.sub.1-C.sub.4 alkyl, aryl, heteroaryl or --NHR.sup.20b;
[0386] R.sup.20b is an amino protecting group; [0387] R.sup.20c is
carbocyclyl optionally substituted with 1-5 R.sup.22; or
heterocarbocyclyl optionally substituted with 1-5 R.sup.22; [0388]
R.sup.21 is selected from the group consisting of: [0389]
C.sub.1-C.sub.20 alkyl, C.sub.2-C.sub.20 alkenyl, C.sub.2-C.sub.20
alkynyl, C.sub.1-C.sub.20 alkoxy, C.sub.1-C.sub.20 thialkoxy,
--OH--CN, halo, haloalkyl, --NH.sub.2, --NH(alkyl),
--N(alkyl).sub.2, --NHC(.dbd.O)O-alkyl, --NHC(.dbd.O)alkyl,
--C(.dbd.O)O-alkyl, --C(.dbd.O)alkyl, --S(.dbd.O)-alkyl,
--S(.dbd.O).sub.2-alkyl, --S(.dbd.O)-aryl, --S(.dbd.O).sub.2-aryl,
carbocyclyl optionally substituted with 1-5 R.sup.22, and
heterocarbocyclyl optionally substituted with 1-5 R.sup.22; [0390]
R.sup.22 is selected from the group consisting of: [0391]
C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10
alkynyl, phenyl, halo, haloalkyl, alkoxy, thialkoxy, amino,
alkylamino, dialkylamino, carboxyl, alkyl-OC(.dbd.O)--,
alkyl-C(.dbd.O)--, aryl-OC(.dbd.O)--, alkyl-OC(.dbd.O)NH--,
aryl-OC(.dbd.O)NH--, alkyl-C(.dbd.O)NH--, alkyl-C(.dbd.O)O--,
(alkyl-O).sub.r-alkyl, HO-(alkyl-O).sub.r-alkyl-, --OH, --SH, --CN,
--N.sub.3, --CNO, --CNS, alkyl-S(.dbd.O)--,
alkyl-S(.dbd.O).sub.2--, H.sub.2NS(.dbd.O)--, and
H.sub.2NS(.dbd.O).sub.2--; and [0392] r is 2, 3, 4, or 5; [0393]
comprising: reacting a compound of Formula (I) wherein R.sup.2 is
--CH.sub.2NH--C(.dbd.O)OCH.sub.2(C.sub.6H.sub.5); with a suitable
hydrogenation reagent for a time and under conditions suitable for
forming the compound of Formula (I) wherein R.sup.2 is
--CH.sub.2NH.sub.2, provided the hydrogenation agent is selective
for the benzyloxycarbonyl group of R.sup.2.
[0394] In some embodiments, the hydrogenation agent is H.sub.2 in
the presence of Pd/C 10% and HCl in 1,4-dioxane.
Boronic Ester/Boronic Acid Conversion
[0395] Compounds of the invention containing boronic esters, such
as pinanediol esters, can be hydrolyzed by any suitable means to
prepare corresponding boronic acid (--B(OH).sub.2) derivatives.
Hydrolysis conditions can include contacting a boronic ester with
excess acid, such as a protic acid like HCl.
[0396] Conversely, boronic acids can be esterified by contacting
the acid compound (--B(OH).sub.2) with an alcohol such as a diol
for sufficient time to produce the corresponding ester. The
esterification reaction can be acid or base catalyzed.
[0397] The invention will be described in greater detail by way of
specific examples. The following examples are offered for
illustrative purposes, and are not intended to limit the invention
in any manner. Those of skill in the art will readily recognize a
variety of noncritical parameters which can be changed or modified
to yield essentially the same results.
EXAMPLES
Example A.1
Synthesis of
(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benz-
odioxaborol-2-yl]-3-methylbutylamine hydrochloride salt
Step 1:
2-(2-methylpropyl)-(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6--
methano-1,3,2-benzodioxaborole
##STR00032##
[0399] A mixture of (+)-pinanediol (23.9 g, 0.140 mol) and
2-methylpropylboronic acid (15 g, 0.147 mol) in diethyl ether (300
ml) was stirred at room temperature for 24 h. The mixture was dried
over anhydrous sodium sulfate and purified by column chromatography
(Silica gel 230-400 mesh), eluting with hexane:ethyl acetate 90:10
mixture. The product was obtained as a clear oil (32.6 g, 94%
yield).
[0400] .sup.1H NMR (DMSO-d.sub.6): 4.28 (1H, dd, J=8.8 Hz, 2.0);
2.30 (1H, m); 2.18 (1H, m); 1.96 (1H, t, J=5.3); 1.86 (1H, m); 1.78
(1H, set, J=6.8); 1.68 (1H, m); 1.30 (3H, s); 1.25 (3H, s); 1.01
(1H, d); 0.9 (6H, d, J=6.6); 0.81 (3H, s); 0.69 (2H, m).
Step 2:
2-[(1S)-1-chloro-3-methylbutyl]-(3aS,4S,6S,7aR)-hexahydro-3a,5,5-t-
rimethyl-4,6-methano-1,3,2-benzodioxaborole
##STR00033##
[0402] A solution of lithium diisopropylamide was prepared by
addition of 10.0 M butyl lithium solution in hexane (25.4 ml, 0.254
mol) to a solution of diisopropylamine (35.7 ml, 0.254 mol) in dry
tetrahydrofuran (60 ml), at -50.degree. C., and allowing the
temperature to rise to -30.degree. C. This solution was transferred
via canula into a solution of
2-(2-methylpropyl)-(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-meth-
ano-1,3,2-benzodioxaborole of Step 1 (50 g, 0.212 mol) and
CH.sub.2Cl.sub.2 (50 ml, 0.848 mol) in dry tetrahydrofuran (700
ml), while keeping the temperature below -70.degree. C. A 1.0 M
solution of dry zinc chloride in diethyl ether (339 ml, 0.339 mol)
was then added over a 30 minutes period while keeping the internal
temperature below -70.degree. C. The reaction mixture was stirred
at -78.degree. C. for 3 hours, then allowed to warm to room
temperature. After removal of the solvents by rotary evaporation
the residue was partitioned between petroleum ether (1000 ml) and a
10% aqueous solution of ammonium chloride (800 ml). The aqueous
layer was further extracted with petroleum ether (300 ml). The
combined organic phases were dried over anhydrous sodium sulfate
and concentrated. The product was obtained as a brown oil (59.0 g,
98% yield) containing about 9% mol/mol of starting material
(.sup.1H-NMR), and was used in the subsequent step without further
purification.
[0403] .sup.1H NMR (DMSO-d.sub.6): 4.43 (1H, dd, J=8.8, 1.8); 3.59
(1H, m); 2.33 (1H, m); 2.21 (1H, m); 2.01 (1H, m); 1.88 (1H, m);
1.84-1.55 (5H, m); 1.34 (3H, s); 1.26 (3H, s); 1.09 (1H, J=10.1);
0.9 (3H, d, J=6.8); 0.87 (3H, d, J=6.4); 0.82 (3H, s).
Step 3:
N,N-Bis(trimethylsilyl)-(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-t-
rimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutylamine
##STR00034##
[0405] A 1.0 M solution of lithium bis(trimethylsilyl)amide in
tetrahydrofuran (189 ml, 0.189 mol) was added, over 30 minutes, to
a solution of crude
2-[(1S)-1-chloro-3-methylbutyl]-(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethy-
l-4,6-methano-1,3,2-benzodioxaborole of Step 2 (59.0 g, 91% purity,
0.189 mol) in tetrahydrofuran (580 ml) while cooling at -78.degree.
C. The reaction mixture was allowed to slowly warm to room
temperature overnight. The solvent was removed by rotary
evaporation and the residue taken up with dry hexane (800 ml). The
resulting suspension was stirred at room temperature for 2 hours,
then the solid was removed by filtration on a celite cake, which
was washed with dry hexane (3.times.100 ml). The filtrate was
concentrated giving a satisfactorily pure product as a brown oil
(79 g) in practically quantitative yield. The product was used for
the subsequent step without further purification.
[0406] .sup.1H NMR (DMSO-d.sub.6): 4.33 (1H, dd, J=1.5 Hz, 8.6);
2.58 (1H, m); 2.29 (1H, m); 2.18 (1H, m); 1.95 (1H, t, J=5.9); 1.85
(1H, m); 1.9-1.55 (3H, m); 1.31 (3H, s); 1.24 (3H, s); 1.17 (1H,
m); 1.01 (1H, d, J=10.6); 0.85 (3H, d, J=6.6), 0.83 (3H, d, J=6.6);
0.80 (3H, s); 0.08 (18H, s).
Step 4:
(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3-
,2-benzodioxaborol-2-yl]-3-methylbutylamine hydrochloride salt
##STR00035##
[0408] To a solution of crude
N,N-Bis(trimethylsilyl)-(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethy-
l-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutylamine of
Step 3 (79 g, 0.193 mol) in a mixture of dioxane (100 ml) and
diethyl ether (200 ml), a 4 N solution of hydrogen chloride in
dioxane (193 ml, 0.772 mol) was added, while cooling at 0.degree.
C. The mixture was then stirred at room temperature for 4 hours and
concentrated. The residue was taken up with anhydrous hexane (500
ml) and a 2 M solution of hydrogen chloride in diethyl ether (48
ml, 0.096 mol) was added. The mixture was stirred at 0.degree. C.
for 1 hour, then concentrated. The residue was taken up with
anhydrous hexane and the resulting suspension was stirred at room
temperature overnight. The solid was collected by filtration and
dried under vacuum affording 38.1 g of product (66% yield). A
second crop (4.13 g, 7% yield) was obtained from the mother
liquors.
[0409] .sup.1H NMR (DMSO-d.sub.6): 7.85 (3H, br); 4.45 (1H, dd,
J=9.2 Hz); 2.78 (1H, m); 2.34 (1H, m); 2.21 (1H, m); 2.01 (1H, t,
J=5.3); 1.89 (1H, m); 1.82-1.65 (2H, m); 1.49 (1H, m); 1.38 (3H,
s); 1.27 (3H, s); 1.12 (1H, d, J=1.12); 0.87 (6H, d, J=6.6); 0.83
(3H, s).
Example A.2
Alternate synthesis of
2-(2-methylpropyl)-(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-
-1,3,2-benzodioxaborole
Step 1:
2-(1-methylethoxy)-(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6--
methano-1,3,2-benzodioxaborole
##STR00036##
[0411] To a solution of (1S,2S,3R,5S)-(+)-Pinanediol (50.0 g, 0.293
mol) in anhydrous tetrahydrofuran (350 ml) triisopropoxy borane was
slowly added while stirring at 0.degree. C. under nitrogen. After 2
h the solvent was removed by rotary evaporation. The oily residue
was redissolved in hexane (150 ml) and the solution was filtered to
remove a very small amount of a white solid. The filtrate was
concentrated by rotary evaporation affording the product as a clear
oil (62.6 g, 90% yield).
[0412] .sup.1H NMR (DMSO-d.sub.6): 4.31-4.20 (2H, m); 2.34-2.16
(2H, m); 1.96 (1H, t, J=5.5); 1.90-1.85 (1H, m); 1.74-1.67 (1H, m);
1.32 (3H, s); 1.31 (1H, d, J=7.6); 1.25 (3H, s); 1.14 (3H, d,
J=6.1); 1.13 (3H, d, J=6.1); 0.81 (3H, s).
Step 2:
2-(2-methylpropyl)-(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6--
methano-1,3,2-benzodioxaborole
##STR00037##
[0414] A 2M solution of isobutyl magnesium bromide in diethyl ether
(131.5 ml, 0.263 mol) was added dropwise, in 1 hour, to a solution
of
2-(1-methylethoxy)-(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-
-1,3,2-benzodioxaborole obtained in Step 1 (62.6 g, 0.263 mol), in
anhydrous tetrahydrofuran (330 ml) while stirring at -78.degree.
C., under nitrogen. The mixture was then allowed to warm to room
temperature, then transferred in a mixture of 2N sulfuric acid (150
ml) and diisopropyl ether (250 ml). After stirring for 10 minutes,
a saturated solution of NaCl was added (100 ml) and the layers were
separated. The organic phase was washed with brine (100 ml), dried
over sodium sulfate and concentrated. The residue was purified by
column chromatography (silica gel) eluting with 5% diethyl ether in
hexane. The product was obtained as a clear oil (38.45 g, 62%
yield).
Example B.1
Carbamic acid 1,1-dimethylethyl ester,
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-metha-
no-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4-[[imino(nit-
roamino)methyl]amino]butyl]
##STR00038##
[0415] Method A: HOAt/HATU
[0416] To a solution of BocNH(NO.sub.2)ArgOH (15.7 g, 49.3 mmol) in
anhydrous DMF (100 ml), HATU
(O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate; 18.7 g, 49.3 mmol) and HOAt
(1-hydroxy-7-azabenzotriazole; 6.71 g, 49.3 mmol) were added. The
mixture was cooled to 0.degree. C. and N-methylmorpholine was added
(13.6 ml, 0.123 mol). After 10 minutes
(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benz-
odioxaborol-2-yl]-3-methylbutylamine hydrochloride salt of Example
A.1 (12.4 g, 41.1 mmol) was added. The cooling bath was removed and
the mixture was stirred at r.t. for 4.5 hours. The mixture was
diluted with ethyl acetate (800 ml), washed with a 2% solution of
citric acid (2.times.150 ml), 2% solution of NaHCO.sub.3
(2.times.150 ml) and 2% solution of NaCl (2.times.150 ml). The
aqueous phases were further extracted with ethyl acetate (150 ml).
The combined organic phases were dried over sodium sulfate and
concentrated. The resulting oily residue was redissolved in ethyl
acetate (500 ml) and the solution was washed with cold water (200
ml). The aqueous phases were further extracted with ethyl acetate
(500 ml). The combined organic phases were dried over sodium
sulfate and concentrated. The residue was dissolved in diethyl
ether (100 ml) an the solution was slowly added to hexane (600 ml)
while stirring. The white solid was collected by filtration (43.4
g) and purified by column chromatography eluting initially with
50:50 hexane:ethyl acetate mixture and then with ethyl acetate. The
fractions containing the product were concentrated, the residue was
dissolved in diethyl ether (100 ml) and the resulting solution was
slowly added to hexane (600 ml) while stirring. The white solid was
collected by filtration (15.2 g, 66% yield).
Method B: IBCF
[0417] To a suspension of BocNH(NO.sub.2)ArgOH (5.82 g, 18.2 mmol)
in anhydrous dichloromethane (100 ml) N-methylmorpholine (2.0 ml,
18.2 mmol) was added. The mixture was cooled to -15.degree. C. then
isobutyl chloroformate was added (2.37 ml, 18.2 mmol). The mixture
was stirred at -15.degree. C. for 10 minutes then
(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benz-
odioxaborol-2-yl]-3-methylbutylamine hydrochloride salt obtained as
in Example A.1 was added (5.0 g, 16.6 mmol), immediately followed
by further N-methylmorpholine (2.0 ml, 18.2 mmol). The reaction
mixture was stirred for 1.5 hours at -15.degree. C., then allowed
to warm to room temperature and partitioned between ethyl acetate
(150 ml), water (150 ml) and 0.1N hydrochloric acid (10 ml). The
organic phase was washed with a saturated solution of NaHCO.sub.3,
dried over anhydrous sodium sulphate and concentrated. The oily
residue (9.25 g) was purified by crystallization from ethyl acetate
affording three crops of satisfactorily pure product (5.03 g, 54%
yield).
[0418] .sup.1H NMR (DMSO-d.sub.6): 8.80 (1H, br); 8.50 (1H, br),
7.87 (2H, br); 7.01 (1H, d, J=7.9), 4.07 (1H, dd, J=7.9); 4.0 (1H,
m); 3.12 (2H, m); 2.55 (1H, m); 2.2 (1H, m); 2.01 (1H, m); 1.83
(1H, t, J=5.1); 1.78 (1H, m); 1.74-1.44 (7H, m); 1.38 (9H, s); 1.33
(1H, d, J=10.3); 1.24 (5H, s); 1.22 (3H, s); 0.84 (6H, d, J=6.6);
0.81 (3H, s)
Example B.2
Carbamic acid 1,1-dimethylethyl ester,
N-[1(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-m-
ethano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxy-
propyl]-
##STR00039##
[0420] Boc-L-threonine (870 mg, 3.97 mmol, 1.2 eq.) was dissolved
in DMF dry (30 ml) at r.t. To this solution, TBTU
(N,N,N',N'-tetramethyl-O-(benzotriazol-1-yl)uronium
tetrafluoroborate; 1270 mg, 3.97 mmol, 1.2 eq.) was added and the
mixture was cooled at 0.degree.-5.degree. C. Then NMM (0.9 ml, 8.27
mmol, 2.5 eq.) and
(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benz-
odioxaborol-2-yl]-3-methylbutylamine hydrochloride salt of Example
A.1 (1000 mg, 3.3 mmol, 1 eq.) were added. The mixture was stirred
at r.t. for 16 h, then was extracted with ethyl acetate (100 ml)
washed with the following solutions: citric acid 2% (50 ml), sodium
bicarbonate 2% (50 ml), NaCl 2% (50 ml). The organic solution was
dried over sodium sulphate anhydrous, filtered and evaporated under
reduced pressure to give 1290 mg of glassy solid. Yield 84.3%. M.p.
25.degree.-30.degree. C.
[0421] .sup.1H NMR (DMSO-d.sub.6): 8.88 (1H, br); 6.49 (1H, d,
J=8.4 Hz); 4.88 (1H, d, J=5.8); 4.05 (1H, dd); 3.93 (1H, m); (1H,
m); 2.51 (1H, m); 2.19 (1H, m); 2.01 (1H, m); 1.83 (1H, t, J=5.9),
1.78 (1H, m); 1.68 (1H, m); 1.62 (1H, m); 1.39 (9H, s); 1.34 (1H,
d, J=10.0); 1.24 (3H, s); 1.22 (3H, s); 1.06 (3H, d, J=6.4); 0.85
(6H, d, J=6.4); 0.80 (3H, s)
Example B.3
Further Intermediate Compounds
[0422] Starting from the appropriate intermediate and following
either of the procedures described in the Example B.1 and B.2, the
intermediates reported below were prepared.
(2S)-2-[(1,1-dimethylethoxycarbonyl)amino]-5-ureidopentanamide,
N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-b-
enzodioxaborol-2-yl]-3-methylbutyl]
##STR00040##
[0424] .sup.1H NMR (DMSO-d.sub.6): 8.85 (1H, br); 7.01 (1H, d,
J=8.0 Hz); 5.9 (1H, t, J=5.7); 5.36 (2H, br); 4.03 (2H, m); 2.93
(2H, m); 2.19 (1H, m); 2.0 (1H, m); 1.83 (1H, t, J=5.3); 1.78 (1H,
m); 1.68 (1H, m); 1.62 (1H, m); 1.52 (2H, m); 1.38 (9H, s); 1.33
(1H, d, J=9.9); 1.24 (3H, s); 1.22 (2H, s); 0.86 (3H, d, J=6.6);
0.84 (3H, d, J=6.6); 0.80 (3H, s).
(2S)-3-(Aminocarbonyl)-2-[(1,1-dimethylethoxycarbonyl)amino]propanamide,
N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-b-
enzodioxaborol-2-yl]-3-methylbutyl]
##STR00041##
[0426] .sup.1H NMR (DMSO-d.sub.6): 8.74 (1H, br); 7.28 (1H, br);
6.95 (2H, m); 4.36 (1H, m); 4.07 (1H, m); 2.55 (1H, m); 2.38 (2H,
m); 2.2 (1H, m); 2.02 (2H, m); 1.84 (1H, t, J=5.5); (1H, m); 1.79
(1H, m); 1.68 (1H, m); 1.63 (1H, m); 1.38 (9H, s); 1.33 (1H, d,
J=10); 1.24 (3H, s); 1.22 (2H, s); 0.85 (3H, d, J=6.4); 0.83 (3H,
d, J=6.4); 0.81 (3H, s).
Carbamic acid benzyl ester,
N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-me-
thano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxyp-
ropyl]
##STR00042##
[0428] M.p. 57-60.degree. C. .sup.1H NMR (DMSO-d.sub.6): 8.66 (1H,
s); 7.40-7.29 (5H, m); 7.09 (1H, d, J=8.75); 5.06 (2H, s); 4.90
(1H, J=5.68); 4.11-3.99 (2H, m); 3.91-3.77 (1H, m); 2.58-2.53 (1H,
m); 2.26-2.14 (1H, m); 2.07-1.97 (1H, s); 1.84 (1H, t, J=5.52);
1.81-1.75 (1H, m); 1.73-1.58 (2H, m); 1.33 (2H, d, J=10.1);
1.27-1.20 (7H, m); 1.06 (3H, t, J=6.27); 0.91-0.79 (9H, m).
Example B.4
(2S)-2-[(1,1-Dimethylethoxycarbonyl)amino]-3-[(4-methylbenzoyl)amino]propa-
namide,
N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano--
1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]-
##STR00043##
[0430]
(2S)-2-[(1,1-Dimethylethoxycarbonyl)amino]-3-[(4-methylbenzoyl)amin-
o]-propanoic acid, (650 mg, 2 mmol, 1.2 eq.) of Example G.6, was
dissolved in DMF dry (15 ml), under nitrogen, and TBTU (640 mg, 2
mmol, 1.2 eq.) was added at r.t. The mixture was cooled at
0.degree.-5.degree. C. with ice bath and NMM (0.55 ml, 5 mmol, 2.5
eq.) and
(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benz-
odioxaborol-2-yl]-3-methylbutylamine hydrochloride salt, (500 mg,
1.65 mmol, 1 eq.) of Example A.1, were added. The mixture was
stirred overnight, poured in water (200 ml) and extracted with
ethyl acetate (100 ml). The organic layer was washed with the
following solutions: citric acid 2% (20 mL), sodium bicarbonate 2%
(20 ml), NaCl 2% (20 ml). The organic solution was dried over
sodium sulphate anhydrous, filtered and evaporated to give 740 mg
of glassy solid (quantitative yield).
[0431] .sup.1H NMR (DMSO-d.sub.6) 8.76 (1H, br); 8.28 (1H, t,
J=5.31 Hz); 7.71 (2H, d, J=7.9); 7.26 (2H, d, J=7.9); 6.97 (1H, d,
J=8.0); 4.27 (1H, m); 4.07 (1H, dd, J=8.2, 1.5); 3.48 (2H, m), 2.58
(1H, m); 2.35 (3H, s); 2.19 (1H, m); 2.02 (1H, m); 1.83 (1H, t,
J=4.9); 1.78 (1H, m); 1.62 (2H, m); 1.35 (12H, m); 1.24 (3H, s);
1.23 (3H, s); 0.82 (3H, d); 0.80 (3H, d); 0.78 (3H, s).
Example B.5
2-S-[(1,1-Dimethylethoxycarbonyl)amino]-3-(hexanoylamino)-propionamide,
N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methan-
o-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]
##STR00044##
[0433]
2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(hexanoylamino)propionic
acid, (300 mg, 1 mmol, 1.2 eq.) of Example G.7 was dissolved in DMF
dry (25 ml), under nitrogen, and TBTU (318 mg, 1 mmol, 1.2 eq.) was
added at r.t. The mixture was cooled at 0.degree.-5.degree. C. with
ice bath and NMM (0.27 ml, 2.47 mmol, 2.47 eq.) and
(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benz-
odioxaborol-2-yl]-3-methylbutylamine hydrochloride salt, (250 mg,
0.82 mmol, 1 eq.) of Example A.1, were added. The mixture was
stirred 3 h, poured in water (150 ml) and extracted with ethyl
acetate (100 ml). The organic layer was washed with the following
solutions: citric acid 2% (50 mL), sodium bicarbonate 2% (50 ml),
NaCl 2% (50 ml). The organic solution was dried over sodium
sulphate anhydrous, filtered and evaporated to give 450 mg of
glassy solid. Yield quantitative.
[0434] Analytical data:
[0435] .sup.1H NMR (DMSO-d.sub.6).
[0436] .delta..sub.H: 8.71 (1H, br d, J=2.6 Hz); 7.73 (1H, br t,
J=5.9 Hz); 6.81 (1H, d, J=8.2); 4.10 (2H, m); 3.24 (2H, m); 2.56
(1H, m); 2.19 (1H, m); 2.03 (3H, m); 1.83 (1H, t, J=5.5); 1.78 (1H,
m); 1.64 (2H, m); 1.47 (2H, m); 1.36 (9H, s); 1.4-1.15 (9H, m);
1.24 (3H, s); 1.21 (3H); 0.83 (9H, m); 0.79 (3H, s)
Example B.6
2-S-[(1,1-Dimethylethoxycarbonyl)amino]-3-(4-fluorosulfonylamino)propionam-
ide,
N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-me-
thano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]
##STR00045##
[0438]
2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(4-fluorosulfonylamino)pr-
opionic acid, (1.39 g, 3.83 mmol, 1.2 eq.) of Example G.8, was
dissolved in DMF dry (20 ml), under nitrogen, and TBTU (1.23 g,
3.83 mmol, 1.2 eq.) was added at r.t. The mixture was cooled at
0.degree.-5.degree. C. with ice bath and NMM (1 ml, 9.57 mmol, 3
eq.) and
(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benz-
odioxaborol-2-yl]-3-methylbutylamine hydrochloride salt, (0.96 g,
3.19 mmol, 1 eq.) of Example A.1, were added. The mixture was
stirred 2 h, poured in water (200 ml) and extracted with ethyl
acetate (100 ml). The organic layer was washed with the following
solutions: citric acid 2% (50 mL), sodium bicarbonate 2% (50 ml),
NaCl 2% (50 ml). The organic solution was dried over sodium
sulphate anhydrous, filtered and evaporated with diethyl ether to
give 1.5 g of white solid. Yield 77%.
[0439] Analytical data:
[0440] .sup.1H NMR (DMSO-d.sub.6).
[0441] .delta..sub.H: 8.54 (1H, d, J=2.9 Hz); 7.91 (2H, m); 7.75
(1H, t, J=5.9); 7.50 (2H, t, J=8.8); 6.83 (1H, d, J=8.4); 4.19 (1H,
br d, J=8.2); 4.14 (1H, m); 3.01 (2H, m); 2.69 (1H, m); 2.25 (1H,
m); 2.09 (1H, m); 1.90 (1H, t, J=5.7); 1.85 (1H, m); 1.8-1.6 (2H,
m); 1.5-1.2 (5H, m); 1.43 (9H, s); 1.29 (6H, s); 0.89 (6H, d,
J=6.4); 0.86 (3H, s).
Example B.7
2-S-[(1,1-Dimethylethoxycarbonyl)amino]-3-(3,4-dimethoxyphenylacetamido)pr-
opionamide,
N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methan-
o-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]
##STR00046##
[0443]
2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(3,4-dimethoxyphenylaceta-
mido)-propionic acid, (0.73 g, 1.90 mmol, 1.2 eq.) of Example G.9,
was dissolved in DMF dry (20 ml), under nitrogen, and TBTU (0.61 g,
1.90 mmol, 1.2 eq.) was added at r.t. The mixture was cooled at
0.degree.-5.degree. C. with ice bath and NMM (0.52 ml, 4.7 mmol,
2.5 eq.) and
(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2--
benzodioxaborol-2-yl]-3-methylbutylamine hydrochloride salt, (0.47
g, 1.6 mmol, 1 eq.) of Example A.1, were added. The mixture was
stirred 2 h, poured in water (200 ml) and extracted with ethyl
acetate (100 ml). The organic layer was washed with the following
solutions: citric acid 2% (50 mL), sodium bicarbonate 2% (50 ml),
NaCl 2% (50 ml). The organic solution was dried over sodium
sulphate anhydrous, filtered and evaporated with diethyl ether to
give 0.95 g of crude that was purified by silica gel chromatography
(eluent ethyl acetate) to give 0.3 g of white foam. Yield 30%.
[0444] Analytical data: TLC silica gel (eluent ethyl acetate 100%,
R.f.=0.50)
[0445] .sup.1H NMR (DMSO-d.sub.6).
[0446] .delta..sub.H: 8.69 (1H, d, J=2.6 Hz); 7.90 (1H, t, J=5.7);
6.85 (2H, m); 6.74 (1H, dd, J=1.5, 8.1); 6.85 (3H, m); 4.12 (2H,
m); 3.73 (3H, s); 3.72 (3H, s); 3.34 (2H, s); 3.31 (2H, m); 2.58
(1H, m); 2.20 (1H, m); 2.03 (1H, m); 1.85 (1H, t, J=5.3); 1.79 (1H,
m); 1.66 (2H, m); 1.38 (9H, s); 1.40-1.15 (3H, m); 1.25 (3H, s);
1.23 (3H, s); 0.83 (6H, d, J=6.6); 0.81 (3H, s).
Example B.8
2-S-[(1,1-Dimethylethoxycarbonyl)amino]-3-(3-phenylureido)propionamide,
N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methan-
o-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]
##STR00047##
[0448]
2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(3-phenylureido)propionic
acid, (0.41 g, 1.26 mmol, 1.2 eq.) of Example G.10, was dissolved
in DMF dry (20 ml), under nitrogen, and TBTU (0.40 g, 1.26 mmol,
1.2 eq.) was added at r.t. The mixture was cooled at
0.degree.-5.degree. C. with ice bath and NMM (0.346 ml, 3.15 mmol,
2.5 eq.) and
(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benz-
odioxaborol-2-yl]-3-methylbutylamine hydrochloride salt, (0.31 g, 1
mmol, 1 eq.) of Example A.1, were added. The mixture was stirred 2
h, poured in water (200 ml) and extracted with ethyl acetate (100
ml). The organic layer was washed with the following solutions:
citric acid 2% (50 mL), sodium bicarbonate 2% (50 ml), NaCl 2% (50
ml). The organic solution was dried over sodium sulphate anhydrous,
filtered and evaporated with diethyl ether (50 ml) to give 0.58 g
of white solid. Yield 96.6%.
[0449] Analytical data: TLC silica gel (eluent ethyl acetate 100%,
R.f.=0.47), m.p. 128.degree.-130.degree. C.
[0450] .sup.1H NMR (DMSO-d.sub.6).
[0451] .delta..sub.H: 8.79 (1H, d, J=2.7 Hz); 8.69 (1H, s); 7.38
(2H, d, J=7.9); 7.22 (2H, t, J=8.1); 7.00 (1H, d, J=8.1); 6.90 (1H,
t, J=7.3); 6.16 (1H, t, J=5.7); 4.12 (2H, m); 3.45 (1H, m); 3.17
(1H, m); 2.60 (1H, m); 2.21 (1H, m); 2.04 (1H, m); 1.85 (1H, t,
J=5.3); 1.79 (1H, m); 1.66 (2H, m); 1.38 (9H, s); 1.40-1.15 (3H,
m); 1.26 (3H, s); 1.23 (3H, s); 0.84 (6H, d, J=6.6); 0.81 (3H,
s).
Example B.9
Synthesis of Further Compounds
[0452] Following the procedures of Examples B.4-B.8, the following
compounds can be prepared by reaction of
(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benz-
odioxaborol-2-yl]-3-methylbutylamine hydrochloride salt of Example
A.1 and intermediates of Examples G.11, G.12 and G.13.
TABLE-US-00001 B.9.1 2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-
(acetamido-)propionamide,N-[(1S)-1-[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-
methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl].
##STR00048## B.9.2 2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(9-
fluorenylmethyloxycarbamoyl)ethyl]-propionamide,N-
[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-
trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]. ##STR00049## B.9.3
2-S-[(1,1-dimethylethoxycarbonyl)amino]-2-
[(pentylureido)ethyl]-N-[(1S)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-
methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-
##STR00050## B.9.4 2-S-[(1,1-dimethylethoxycarbonyl)amino]-2-
(methanesolfonamido)ethyl]-N-[(1S)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-
methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-
##STR00051## B.9.5 2-S-[(1,1-dimethylethoxycarbonyl)amino]-2-
[(ethoxycarbonylsuccinyl]-amide)ethyl]-N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-
trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]- ##STR00052## B.9.6
2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-
(benzyloxycarbamoyl)ethyl]-propionamide,N-[(1S)-1-
[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-
4,6-mediano-1,3,2-benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]. ##STR00053## B.9.7
2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-[2-(1H-
pyrazol)ethyl]-N-[(1S)-1-[[[(1R)-1-[(3aS,aS,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl-]- 3-methylbutyl]amino]carbonyl]
##STR00054##
Example B.10
Carbamic acid 1,1-dimethylethyl ester,
N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-me-
thano-1,3,2-benzodioxaborol-2-yl]-1-methylbutyl]amino]carbonyl]-methyl
##STR00055##
[0454] This compound has been prepared following the procedure of
Example B.1 Method B starting from
(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benz-
odioxaborol-2-yl]-3-methylbutylamine hydrochloride salt of Example
A.1 and commercially available
N-(1,1-dimethylethoxycarbonyl)glycine.
[0455] .sup.1H-NMR (DMSO-d.sub.6): 8.84 (1H, s); 7.08 (1H, t,
J=5.93 Hz); 4.06 (1H, d, J=7.48 Hz); 3.67 (2H, t, J=5.32 Hz);
2.60-2.48 (1H, m); 2.24-2.16 (1H, m); 2.06-1.96 (1H, m); 1.84 (1H,
t, J=5.50 Hz); 1.82-1.76 (1H, m); 1.74-1.58 (2H, m); 1.39 (10H,
bs); 1.23 (9H, d, J=8.18 Hz); 0.87-0.83 (6H, m); 0.82 (3H, bs).
Example C.1
(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]pentanamide,
N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-b-
enzodioxaborol-2-yl]-3-methylbutyl]; hydrochloride salt
##STR00056##
[0456] Method A
[0457] A 4 N solution of hydrogen chloride in dioxane (15 ml) was
added to a solution of carbamic acid 1,1-dimethylethyl ester,
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-metha-
no-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4-[[imino(nit-
roamino)methyl]amino]butyl]- of Example B.1, (4.04 g, 7.06 mmol) in
a mixture of dioxane (40 ml) and diethyl ether (7 ml), while
cooling at 0.degree. C. The reaction mixture was allowed to warm to
room temperature and stirred for further 4 hours. The solvent was
removed by rotary evaporation, the residue was treated with diethyl
ether (50 ml) and the mixture was stirred at r.t. for three days.
The resulting solid was collected by filtration affording 3.18 g of
pure product (90% yield)
Method B
[0458] Carbamic acid 1,1-dimethylethyl ester,
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-metha-
no-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]-amino]-carbonyl]-4-[[imino(n-
itroamino)-methyl]-amino]butyl]- of Example B.1, (3 g, 5.3 mmol)
was dissolved in Et.sub.2O (40 mL) and a solution of about 10% HCl
in Et.sub.2O (20 mL) was added dropwise at 0.degree. C. under
nitrogen. The reaction mixture was allowed to warm to room
temperature and to stir for further 5 hours. The solvent was
decanted and the residue, washed twice with Et.sub.2O (20 mL), was
dried in vacuo to give the title compound as a white powder (2.43
g, yield 91%).
[0459] .sup.1H NMR (DMSO-d.sub.6): 8.56 (2H, br); 8.22 (3H, br);
7.97 (2H, br); 4.28 (1H, dd, J=8.6 Hz, 2.01); 3.77 (1H, m); 3.04
(1H, m); 2.28 (1H, m); 2.11 (2H, m), 1.92 (1H, t, J=5.5); 1.83 (1H,
m); 1.79-1.59 (4H, m); 1.59-1.37 (3H, m); 1.31 (4H, s); 1.24 (3H,
s); 1.19 (1H, d, J=10.4); 0.88 (3H, d, J=6.0); 0.86 (3H, d, J=6.0);
0.81 (3H, s).
Example C.2
Boronic acid,
[(1R)-1-[[(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]ami-
no]-3-methylbutyl], hydrochloride salt
##STR00057##
[0461] Carbamic acid 1,1-dimethylethyl ester,
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-metha-
no-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4-[[imino(nit-
roamino)methyl]amino]butyl]- of Example B.1, (3.1 g, 5.48 mmol) was
carefully dissolved, under nitrogen at 0.degree. C., in 20 mL of
HCl 37%; the resultant mixture was allowed to warm to room
temperature and to stir overnight. The reaction mixture was washed
with Et.sub.2O until complete removal of pinanediol; the aqueous
solution was concentrated to dryness and dried in vacuo to afford
1.82 g (4.93 mmol, yield 90%) of the title compound, used without
further purification.
[0462] .sup.1H NMR (DMSO+D.sub.2O+TFA): 3.78 (m, 1H); 3.19 (m, 2H);
3.09 (m, 1H); 1.71 (m, 2H); 1.70-1.48 (m, 3H); 1.49-1.23 (m, 2H);
0.89 (d, J=5.8 Hz, 3H); 0.88 (d, J=5.8 Hz, 3H).
Example C.3
Synthesis of Further Intermediates
[0463] Starting from the appropriate intermediate and following
either the procedures described in the Example C.1 the
intermediates reported below were prepared:
(2S,3R)-2-Amino-3-hydroxybutanamide,
N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-b-
enzodioxaborol-2-yl]-3-methylbutyl]-, hydrochloride salt
##STR00058##
[0465] .sup.1H NMR (DMSO-d.sub.6) .delta..sub.H: 8.62 (1H, d, J=5.0
Hz); 8.17 (3H, d, J=3.5); 4.28 (1H, dd, J=8.8, 1.8); 3.78 (1H, m);
3.52 (1H, m); 3.00 (1H, m); 2.28 (1H, m); 2.10 (1H, m); 1.92 (1H,
t, J=5.7); 1.84 (1H, m); 1.75-1.62 (2H, m); 1.43 (1H, m); 1.31 (3H,
s); 1.25 (3H, s); 1.22 (1H, d, J=10.6); 1.14 (3H, d, J=6.2); 0.88
(3H, d, J=6.4); 0.86 (3H, d, J=6.4); 0.81 (3H, s)
(2S)-2-Amino-5-ureidopentanamide,
N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-b-
enzodioxaborol-2-yl]-3-methylbutyl]; hydrochloride salt
##STR00059##
[0467] .sup.1H NMR (DMSO-d.sub.6) 8.51 (1H, d, J=5.1 Hz); 8.17 (3H,
br); 6.1 (1H, br); 4.27 (1H, dd, J=8.6 Hz, 1.8); 3.73 (1H, m); 2.99
(1H, m); 2.94 (2H, t); 2.27 (1H, m); 2.10 (1H, m), 1.92 (1H, t,
J=5.5); 1.82 (1H, m); 1.75-1.15 (9H, m); 1.30 (3H, s); 1.23 (3H,
m); 0.87 (3H, d, J=6.0); 0.85 (3H, d, J=6.0); 0.80 (3H, s).
(2S)-2-Amino-3-carbamoylpropanamide,
N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-b-
enzodioxaborol-2-yl]-3-methylbutyl]; hydrochloride salt
##STR00060##
[0469] .sup.1H-NMR (DMSO-d6): 8.46-8.41 (1H, m); 8.06 (3H, bs);
7.67 (1H, s); 7.26 (1H, s); 4.30-4.25 (1H, m); 4.08-4.02 (1H, m);
2.96 (1H, m); 2.60-2.52 (1H, m); 2.36-2.24 (1H, m); 2.20-2.10 (1H,
m); 1.95 (1H, t, J=5.5); 1.88-1.83 (1H, m); 1.75-1.60 (2H, m);
1.46-1.36 (1H, m); 1.32 (3H, s); 1.30-1.18 (6H, m); 0.86 (6H, t,
J=6.7); 0.82 (3H, s).
2-Aminoacetamide,
N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-me-
thano-1,3,2-benzodioxaborol-2-yl]-1-methylbutyl]; Hydrochloride
salt
##STR00061##
[0471] .sup.1H-NMR (DMSO-d6): 8.50 (1H, s); 8.20 (3H, bs); 4.29
(1H, d, J=7.70 Hz); 3.15 (2H, bs); 3.05 (1H, s); 2.36-2.24 (1H, m);
2.20-2.10 (1H, m); 1.95 (1H, t, J=5.38 Hz); 1.85 (1H, s); 1.75-1.60
(2H, m); 1.50-1.38 (1H, m); 1.35-1.30 (3H, m); 1.28-1.25 (4H, m);
1.24-1.17 (1H, m); 0.86 (6H, t, J=5.94 Hz); 0.84 (3H, s).
Example C.4
(2S)-2-Amino-3-[(4-methylbenzoyl)amino]propanamide,
N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-b-
enzodioxaborol-2-yl]-3-methylbutyl]-, hydrochloride salt
##STR00062##
[0473] (2
S)-2-[(1,1-Dimethylethoxycarbonyl)amino]-3-[(4-methylbenzoyl)-am-
ino]-propanamide,
N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-b-
enzodioxaborol-2-yl]-3-methylbutyl]-, Example B.4, (740 mg, 1.65
mmol, 1 eq.), was dissolved in 1,4-dioxane (20 ml). To this
solution, HCl 4N in 1,4-dioxane (5 ml, 19.8 mmol, 12 eq.) was added
and the solution stirred overnight at r.t. The solvent was removed
under reduced pressure to give 800 mg of a glassy solid
(quantitative yield).
[0474] .sup.1H NMR (DMSO-d.sub.6) 8.63 (1H, d, J=5.5 Hz); 8.38 (1H,
t, J=8.4 Hz); 8.34 (3H, br); 7.80 (2H, t, J=8.2); 7.28 (2H, d,
J=8.2 Hz); 4.15 (1H, dd, J=8.8, 1.8); 4.02 (1H, br); 3.66 (1H, m);
3.55 (1H, m); 2.99 (1H, m); 2.35 (3H, s); 2.19 (1H, m); 2.06 (1H,
m); 1.86 (1H, t, J=5.7); 1.80 (1H, m); 1.64 (2H, m); 1.41 (1H, m);
1.33-1.19 (2H, m); 1.27 (3H, s), 1.21 (3H, s); 1.16 (1H, d,
J=10.6); 0.82 (3H, d); 0.80 (3H, d); 0.78 (3H, s)
Example C.5
2-S-amino-3-(hexanoylamino)-propionamide,
N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methan-
o-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl],
hydrochloride salt
##STR00063##
[0476]
2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(hexanoylamino)propionami-
de,
N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-met-
hano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl], of
Example B.5, (450 mg, 0.8 mmol, 1 eq.), was dissolved in
1,4-dioxane (15 ml). To this solution, HCl 4N in 1,4-dioxane (2.45
ml, 0.98 mmol, 12 eq.) was added and the solution stirred overnight
at r.t. The solvent was removed under reduced pressure to give 400
mg of a glassy solid. Yield quantitative.
[0477] Analytical data: .sup.1H NMR (DMSO-d.sub.6).
[0478] .delta..sub.H: 8.54 (1H, d, J=5.3 Hz); 8.18 (3H, br); 7.74
(1H, t, J=5.7); 4.29 (1H, dd, J=1.8, 8.8); 3.83 (1H, m); 3.40 (2H,
m); 3.00 (1H, m); 2.29 (1H, m); 2.11 (1H, m); 2.08 (2H, t, J=7.5);
1.93 (1H, t, J=5.5); 1.84 (1H, m); 1.75-1.15 (11H, m); 1.32 (3H,
s); 1.24 (3H, s); 0.86 (3H, d, J=6.6); 0.84 (3H, d, J=6.6); 0.81
(3H, s).
Example C.6
2-S-amino-3-(4-fluorosulfonylamino)propionamide,
N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methan-
o-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl],
hydrochloride salt
##STR00064##
[0480]
2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(4-fluorosulfonylamino)pr-
opionamide,
N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methan-
o-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl], of
Example B.6, (0.7 g, 1.14 mmol, 1 eq.), was dissolved in
1,4-dioxane (20 ml). To this solution, HCl 4N in 1,4-dioxane (3.4
ml, 13.68 mmol, 12 eq.) was added and the solution stirred
overnight at r.t. The solvent was removed under reduced pressure to
give 440 mg of a white solid. Yield 71%. Analytical data:
[0481] .sup.1H NMR (DMSO-d.sub.6).
[0482] .delta..sub.H: 8.54 (1H, d, J=5.5 Hz); 8.26 (3H, br); 7.89
(3H, m); 7.48 (3H, t, J=8.8); 4.26 (1H, dd, J=1.3, 8.6); 3.84 (1H,
m); 3.06 (2H, m); 2.97 (1H, m); 2.25 (1H, m); 2.03 (1H, m); 1.83
(2H, m); 1.64 (2H, m); 1.42 (1H, m); 1.35-1.15 (3H, m); 1.28 (3H,
s); 1.22 (3H, s); 1.11 (1H, d, J=10.8); 0.85 (6H, m); 0.80 (3H,
s).
Example C.7
2-S-amino-3-(3,4-dimethoxyphenylacetamido)propionamide,
N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methan-
o-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl],
hydrochloride salt
##STR00065##
[0484]
2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(3,4-dimethoxyphenylaceta-
mido)-propionamide,
N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methan-
o-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl], of
Example B.7, (0.3 g, 0.47 mmol, 1 eq.), was dissolved in
1,4-dioxane (20 ml). To this solution, HCl 4N in 1,4-dioxane (1.43
ml, 5.71 mmol, 12 eq.) was added and the solution stirred overnight
at r.t. The solvent was removed under reduced pressure, diethyl
ether was added and evaporated to give 230 mg of a white solid.
Yield 85%.
[0485] Analytical data:
[0486] .sup.1H NMR (DMSO-d.sub.6).
[0487] .delta..sub.H: 8.57 (1H, br); 8.12 (3H, br); 7.91 (1H, t,
J=5.7 Hz); 6.86 (2H, m); 6.76 (1H, dd, J=1.8, 8.2); 4.26 (1H, br d,
J=7.3); 3.82 (1H, m); 3.72 (3H, s); 3.71 (3H, s); 3.36 (2H, s);
3.34 (2H, m); 2.99 (1H, m); 2.26 (1H, m); 2.10 (1H, m); 1.92 (1H,
t, J=5.3); 1.83 (1H, m); 1.67 (2H, m); 1.45-1.15 (3H, m); 1.31 (3H,
s); 1.23 (3H, s); 0.86 (3H, d, J=6.6); 0.84 (3H, d, J=6.6); 0.80
(3H, s).
Example C.8
2-S-amino-3-(3-phenyl-ureido)-propionamide,
N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methan-
o-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl],
hydrochloride salt
##STR00066##
[0489]
2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(3-phenylureido)propionam-
ide,
N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-me-
thano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl], of
Example B.8, (0.58 g, 0.1 mmol, 1 eq.), was dissolved in
1,4-dioxane (25 ml). To this solution, HCl 4N in 1,4-dioxane (3 ml,
12.1 mmol, 12 eq.) was added and the solution stirred overnight at
r.t. The solvent was removed under reduced pressure, diethyl ether
was added and evaporated to give 0.52 g of desired product. Yield
100%.
[0490] Analytical data:
[0491] .sup.1H NMR (DMSO-d.sub.6).
[0492] .delta..sub.H: 8.82 (1H, s); 8.59 (1H, d, J=5.7 Hz); 8.18
(3H, br); 7.40 (2H, d, J=7.9); 7.22 (2H, t, J=8.1); 6.90 (1H, t,
J=7.3); 6.31 (1H, t, J=5.7); 4.26 (1H, dd, J=1.5, 8.6); 3.89 (1H,
m); 3.48 (1H, m); 3.36 (1H, m); 3.01 (1H, m); 2.24 (1H, m); 2.10
(1H, m); 1.92 (1H, t, J=5.3); 1.82 (1H, m); 1.67 (2H, m); 1.50-1.15
(3H, m); 1.31 (3H, s); 1.21 (3H, s); 0.85 (3H, d, J=6.6); 0.84 (3H,
d, J=6.6); 0.79 (3H, s).
Example C.9
Synthesis of Further Compounds
[0493] Following the procedures of Examples C.4-C.8, the following
compounds can be prepared starting from intermediates of Example
B.9.
TABLE-US-00002 C.9.1
2-S-amino-3-(acetamido)-propionamide,N-[(1S)-1-[[(1R)-
1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-
methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl],
HCl salt. ##STR00067## C.9.2
2-S-amino-3-(9-fluorenylmethyloxycarbamoyl)-
propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl], HCl salt.
##STR00068## C.9.3
2-S-amino-3-(pentylureido)-propionamide,N-[(1S)-1-
[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-
4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl], HCl salt. ##STR00069## C.9.4
2-S-amino-3-(methanesolfonamido)-propionamide,N-
[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-
trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl], HCl salt. ##STR00070## C.9.5
2-S-amino-3-[(ethoxycarbonylsuccinyl]-amide)ethyl]-)-
propionamide,N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl], HCl salt.
##STR00071## C.9.6 2-S-amino-3-(benzyloxycarbamoyl)-propionamide,N-
[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-
trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl], HCl salt. ##STR00072## C.9.7
3-[2-(1H-pyrazol)ethyl]-N-[(1S)-1-[[[(1R)-1-
[(3aS,aS,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-
methano-1,3,2-benzodioxaborol-2-yl-]- 3-methylbutyl]amino]carbonyl]
HCl salt. ##STR00073##
Example D.1
Decanamide,
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-metha-
no-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4-[[imino(nit-
roamino)methyl]amino]butyl]-
##STR00074##
[0495] To a solution of decanoic acid (0.84 g, 4.83 mmol) in
anhydrous DMF (30 ml) HATU (1.84 g, 4.83 mmol) and HOAt (0.66 g,
4.83 mmol) were added. After stirring at room temperature for 15
minutes the mixture was cooled at 0.degree. C. and
N-methylmorpholine (1.33 ml, 12.1 mmol) was added. After further 20
minutes (2S)-2-amino-5-[[imino(nitroamino)methyl]amino]pentanamide,
N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-b-
enzodioxaborol-2-yl]-3-methylbutyl]-hydrochloride salt of Example
C.1 (2.2 g, 4.03 mmol) was added. The mixture was allowed to warm
to room temperature and stirred for 5 hours, then diluted with
ethyl acetate (150 ml), washed with a 2% solution of citric acid
(2.times.100 ml), 2% solution of NaHCO.sub.3 (2.times.100 ml), and
2% solution of NaCl (2.times.100 ml). The organic phases were dried
over sodium sulfate and concentrated. The residue was purified by
column chromatography eluting with AcOEt/n-Hexane mixtures from
80/20 to 100/0. The resulting solid was triturated with diethyl
ether, collected by filtration and dried under vacuum giving 1.8 g
of product (72% yield).
[0496] M.P. 89-94.degree. C.
TABLE-US-00003 El. Anal. Calculated: C 59.99% H 9.26% N 13.54%
Found C 59.47% H 9.51% N 13.42%
[0497] .sup.1H NMR (DMSO-d.sub.6): 8.82 (1H, d, J=2.7 Hz); 8.53
(1H, br); 7.99 (1H, d, J=8.05); 7.88 (2H, br); 4.33 (1H, m); 4.08
(1H, dd, J=1.6, 8.6); 3.14 (2H, m); 2.56 (1H, m); 2.20 (1H, m);
2.11 (2H, m); 2.01 (1H, m); 1.84 (1H, t, J=5.7); 1.79 (1H, m);
1.74-1.58 (3H, m); 1.57-1.39 (5H, m); 1.32 (1H, d, J=9.9); 1.24
(19H, m); 0.85 (9H, m); 0.80 (3H, s).
[0498] Starting with the
(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-pentanamide,
N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-b-
enzodioxaborol-2-yl]-3-methylbutyl]hydrochloride salt of Example
C.1 and the appropriate carboxylic acids, further compounds
prepared fundamentally in accordance with the above experimental
procedures are reported in Table D-1.
TABLE-US-00004 Ex # Structure Chemical Name and Analytical Data
D.1.1 ##STR00075## Chemical Name:
Naphthalen-2-carboxamide,N-[(1S)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-
4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data:
1H-NMR(DMSO-d6): 8.97 (1H, d, J = 2.8 Hz); 8.71 (1H, d, J = 8.0
Hz); 8.54 (1H, br); 8.50 (1H, s); 8.1-7.9 (4H, m); 7.85 (2H, br);
7.6 (2H, m); 4.63 (1H, m); 4.09 (1H, m); 3.20 (2H, m); 2.61 (1H,
m); 2.20 (1H, m); 2.01 (1H, m); 1.9-1.2 (11H, m); 1.23 (3H, s);
1.21 (3H, s); 0.85 (6H, d, J = 6.6): 0.79 (3H, s). D.1.2
##STR00076## Chemical Name:
2-Pyrazinecarboxamide,N-[(1S)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-
4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[imino(nitroamino)methyl]amino]butyl]- Analytical Data:
1H-NMR(DMSO-d6): 9.18 (1H, d, J = 1.3 Hz); 8.89 (1H, d, J = 2.4);
8.8-8.65 (3H, m): 8.5 (2H, br); 4.59 (1H, m); 4.15 (1H, dd, J =
1.8, 8.6); 3.14 (2H, m); 2.72 (1H, m); 2.20 (1H, m); 2.02 (1H, m);
1.9-1.2 (11H, m); 1.23 (3H, s); 1.21 (3H, s); 0.83 (6H, 2 d, J =
6.6); 0.79 (3H, s). D.1.3 ##STR00077## Chemical Name:
3-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-
propanamide,N-[(1S)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-
4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: 1H-NMR
(DMSO-d6): 8.79 (1H, br); 8.51 (1H, br); 8.44 (1H, d, J = 7.8 Hz);
8.2-7.6 (2H, br); 7.85 (4H, m); 4.30 (1H, m); 4.08 1H, dd, J = 1.8,
8.6); 3.78 (2H, t, J = 6.3); 3.11 (2H, m); 2.59 (3H, m); 2.20 (1H,
m); 2.01 (1H, m); 1.9-1.2 (11H, m); 1.23 (3H, s); 1.22 (3H, s);
0.84 (6H, d, J = 6.6); 0.80 (3H, s). D.1.4 ##STR00078## Chemical
Name: 4-Butylbenzamide,N-[(1S)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-
4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data:
1H-NMR(DMSO-d6): 8.93 (1H, d, J = 2.9 Hz); 8.51 (1H, br); 8.24 (1H,
d, J = 7.8); 8.2-7.6 (2H, br); 7.86 (2H, d, J = 8.2); 7.29 (2H, d,
J = 8.2); 4.56 (1H, m); 4.07 1H, dd, J = 1.8, 8.6); 3.16 (2H, m);
2.63 (2H, t, J = 7.7); 2.57 (1H, dt, J = 2.5, 7.1); 2.20 (1H, m);
2.01 (1H, m); 1.9-1.2 (15H, m); 1.23 (3H, s); 1.22 (3H, s); 0.90
(3H, d, J = 7.3); 0.84 (6H, d, J = 6.6); 0.80 (3H, s). D.1.5
##STR00079## Chemical Name: 3-[(1,1-
dimethylethoxy)carbonylamino]benzamide,
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl]- Analytical Data: 1H-NMR
(DMSO-d6): 9.48 (1H, s); 8.88 (1H, d, J = 2.8 Hz); 8.51 (1H, br);
8.42 (1H, d, J = 8.0); 7.6-8.4 (2H, br): 7.97 (1H, s); 7.55 (1H,
dd, J = 7.8, 1.1); 7.47 (1H, d, J = 7.8); 7.34 (1H, t, J = 7.8);
4.55 (1H, m); 4.09 (1H, dd, J = 1.8, 8.6); 3.17 (2H, m); 2.60 (1H,
dt, J = 2.9, 8.4); 2.20 (1H, m); 2.02 (1H, m); 1.9-1.2 (11H, m);
1.48 (9H, s); 1.23 (3H, s); 1.21 (3H, s); 0.85 (6H, d, J = 6.6);
0.80 (3H, s). D.1.6 ##STR00080## Chemical Name:
2-(2-methoxyethoxy)acetamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-
trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-
yl]-3-methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl Analytical Data: 1H-NMR
(DMSO-d6): 8.74 (1H, d, J = 2.8 Hz); 8.51 (1H, br); 8.2-7.4 (2H,
br); 7.69 (1H, d, J = 8.6); 4.39 (1H, m); 4.12 (1H, dd, J = 1.8,
8.6); 3.91 (2H, s); 3.57 (2H, m); 3.46 (2H, t, J = 4.6); 3.26 (3H,
s); 3.13 (2H, m); 2.63 (1H, m); 2.21 (1H, m); 2.03 (1H, m); 1.9-1.2
(11H, m); 1.24 (3H, s); 1.21 (3H, s); 0.85 (3H, d, J = 6.6); 0.83
(3H, d, J = 6.6); 0.80 (3H, s). D.1.7 ##STR00081## Chemical Name:
2-[2-(2-methoxyethoxy)ethoxy]acetamide,N-
[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl Analytical Data: 1H-NMR
(DMSO-d6): 8.74 (1H, d, J = 2.8 Hz); 8.52 (1H, br); 8.2-7.6 (2H,
br); 7.69 (1H, d, J = 8.6); 4.40 (1H, m); 4.11 (1H, dd, J = 1.8,
8.6); 3.91 (2H, s); 3.6-3.4 (8H, m); 3.23 (3H, s); 3.13 (2H, m);
2.63 (1H, m); 2.20 (1H, m); 2.02 (1H, m); 1.9-1.2 (11H, m); 1.24
(3H, s); 1.21 (3H, s); 0.84 (3H, d, J = 6.6); 0.83 (3H, d, J =
6.6); 0.79 (3H, s). D.1.8 ##STR00082## Chemical Name:
(E)-3-(Ethoxycarbonyl)acrylamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-
trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-
yl]-3-methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: 1H-NMR
(DMSO-d6): 8.78 (1H, d, J = 8.6 Hz); 8.77 (1H, s); 8.55 (1H, br);
8.3-7.6 (2H, br); 7.12 (1H, d, J = 15.5); 6.58 (1H, d, J = 15.5);
4.45 (1H, m); 4.19 (2H, q, J = 7.1); 4.12 (1H, dd, J = 1.8, 8.6);
3.15 (2H, m); 2.63 (1H, dt, J = 3.3, 8.6); 2.21 (1H, m); 2.04 (1H,
m); 1.9-1.2 (11H, m); 1.25 (3H, s); 1.24 (3H, t, J = 6.9); 1.23
(3H, s); 0.85 (3H, d, J = 6.6); 0.83 (3H, d, J = 6.6); 0.80 (3H,
s). D.1.9 ##STR00083## Chemical Name:
2-Piperidin-1-yl-acetamide,N-[(1S)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-
4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: 1H-NMR
(DMSO-d6): 8.79 (1H, d, J = 1.8 Hz); 8.53 (1H, br); 8.3-7.5 (2H,
br); 7.79 (1H, br); 4.37 (1H, m); 4.12 (1H, dd, J = 1.8, 8.6); 3.13
(2H, m); 2.87 (2H, br); 2.62 (1H, m); 2.36 (4H, m); 2.20 (1H, m);
2.03 (1H, m); 1.9-1.2 (17H, m); 1.24 (3H, s); 1.21 (3H, s); 0.83
(6H, d, J = 6.6); 0.79 (3H, s). D.1.10 ##STR00084## Chemical Name:
4-(1-Methyl-piperidin-4-yl)-butanamide,N-
[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: 1H-NMR
(DMSO-d6): 8.82 (1H, d, J = 2.7 Hz); 8.51 (1H, br); 8.01 (1H, d, J
= 8.0 Hz); 8.3-7.5 (2H, br); 6.94 (1H, t, J = 5.8): 4.33 (1H, m);
4.07 (1H, dd, J = 1.8, 8.6); 3.13 (2H, m); 2.78 (2H, br); 2.68 (3H,
br s); 2.55 (1H, m); 2.19 (1H, m); 2.10 (2H, t, J = 7.5); 2.00 (1H,
m); 1.85-1.1 (22H, m); 1.23 (3H, s); 1.21 (3H, s); 0.83 (6H, 2 d, J
= 6.6); 0.79 (3H, s). D.1.11 ##STR00085## Chemical Name:
2-Acetylamino-acetamide,N-[(1S)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-
4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: 1H-NMR
(DMSO-d6): 8.67 (1H, d, J = 2.7 Hz); 8.51 (1H, br); 8.14 (1H, t, J
= 5.7); 8.08 (1H, d, J = 8.0 Hz); 8.3-7.5 (2H, br); 4.34 (1H, m);
4.09 (1H, dd, J = 1.8, 8.6); 3.68 (2H, m); 3.13 (2H, m); 2.56 (1H,
m); 2.20 (1H, m); 2.01 (1H, m); 1.84 (3H, s); 1.85-1.2 (11H, m);
1.24 (3H, s); 1.21 (3H, s); 0.83 (6H, d, J = 6.6); 0.79 (3H,
s).
[0499] Following the above described procedure for Example D.1 and
using as starting material the
(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]pentanamide,
N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-b-
enzodioxaborol-2-yl]-3-methylbutyl]-hydrochloride salt of Example
C.1 and the appropriate carboxylic acids, the compounds reported in
Table D-1A are prepared.
TABLE-US-00005 TABLE D-1A Ex # Structure Chemical Name and
Analytical Data D.1.12 ##STR00086## Chemical Name:
6-Benzenesulfonylaminohexanamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-
trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-
yl]-3-methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: 1H-NMR
(DMSO-d6): 8.83 (1H, d, J = 2.8 Hz); 8.51 (1H, br); 7.97 (1H, d, J
= 7.8 Hz); 8.2-7.6 (2H, br); 7.77 (2H, m); 7.65-7.5 (4H, m); 4.31
(1H, m); 4.05 (1H, dd, J = 1.8, 8.6); 3.12 (2H, m); 2.69 (2H, q, J
= 7.0); 2.54 (1H, m); 2.20 (1H, m); 2.05 (2H, t, J = 7.5); 2.01
(1H, m); 1.85-1.1 (21H, m); 1.22 (3H, s); 1.21 (3H, s); 0.82 (6H,
d, J = 6.6); 0.79 (3H, s). D.1.13 ##STR00087## Chemical Name:
8-(Ethanesulfonylamino)octanamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7 aR)-hexahydro-3a,5,5-
trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-
yl]-3-methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl Analytical Data: 1H-NMR
(DMSO-d6): 8.81 (1H, br s); 8.51 (1H, br); 7.98 (1H, d, J = 7.8
Hz); 8.3-7.5 (2H, br); 6.93 (1H, t, J = 5.7): 4.32 (1H, m); 4.06
(1H, dd, J = 1.8, 8.6); 3.13 (2H, m); 2.95 (2H, q, J = 7.3); 2.87
(2H, q, J = 6.7); 2.55 (1H, m); 2.19 (1H, m); 2.10 (2H, t, J =
7.0); 2.00 (1H, m); 1.85-1.1 (17H, m); 1.23 (3H, s); 1.21 (3H, s);
1.16 (3H, t, J = 7.3); 0.83 (6H, d, J = 6.6); 0.79 (3H, s). D.1.14
##STR00088## Chemical Name:
6-(Ethanesulfonylamino)hexanamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-
trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-
yl]-3-methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: 1H-NMR
(DMSO-d6): 8.83 (1H, d, J = 2.7 Hz); 8.51 (1H, br); 8.00 (1H, d, J
= 8.0 Hz); 8.3-7.5 (2H, br); 6.94 (1H, t, J = 5.8): 4.32 (1H, m);
4.06 (1H, dd, J = 1.8, 8.6); 3.13 (2H, m); 2.95 (2H, q, J = 7.3);
2.87 (2H, q, J = 6.7); 2.55 (1H, m); 2.19 (1H, m); 2.10 (2H, t, J =
7.5); 2.00 (1H, m); 1.85- 1.1 (17H, m); 1.24 (3H, s); 1.21 (3H, s);
1.16 (3H, t, J = 7.5); 0.83 (6H, d, J = 6.6); 0.79 (3H, s).
Example D.2
10-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-decanamide,
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-metha-
no-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4-[[imino(nit-
roamino)methyl]amino]butyl]-;
##STR00089##
[0501] To a solution of
10-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-decanoic acid (353 mg,
1.11 mmol), prepared according to Example G.1, in anhydrous
dichloromethane (10 ml), N-methylmorpholine was added (122 .mu.l,
1.11 mmol). The mixture was cooled to -15.degree. C., then isobutyl
chloroformate (144 .mu.l, 1.11 mmol) was slowly added. After 15
minutes (2S)-2-amino-5-[[imino(nitroamino)methyl]amino]pentanamide,
N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-b-
enzodioxaborol-2-yl]-3-methylbutyl]-hydrochloride salt of Example
C.1 (508 mg, 1.01 mmol) and further N-methylmorpholine (122 .mu.l,
1.11 mmol) were added. The reaction mixture was stirred at -15 to
10.degree. C. for 4 h, then concentrated to small volume and
partitioned between ethyl acetate (20 ml) and water (10 ml). The
aqueous phase was further extracted with ethyl acetate (10 ml). The
combined organic phases were dried over sodium sulfate and
concentrated. The residue was taken up with ethyl acetate (3 ml)
and the solution was dropwise added to hexane (120 ml) while
stirring at room temperature. The solid was collected by
decantation and dried under vacuum (730 mg, 94%).
[0502] .sup.1H NMR (DMSO-d.sub.6): 8.81 (1H, d, J=2.7 Hz); 8.52
(1H, br); 7.98 (1H, d, J=8.05); 7.88 (2H, br); 7.85 (4H, m); 4.34
(1H, m); 4.06 (1H, dd, J=7.1); 3.56 (2H, t, J=7.14); 3.14 (2H, m);
2.55 (1H, m); 2.19 (1H, m); 2.10 (2H, t, J=7.14); 2.0 (1H, m); 1.82
(1H, t, J=5.7); 1.78 (1H, m); 1.73-1.35 (10H, m); 1.31 (1H, d,
J=9.9); 1.24 (19H, m); 0.84 (9H, m); 0.79 (3H, s).
[0503] Further compounds prepared fundamentally in accordance with
the above experimental procedures are reported in Table D-2.
TABLE-US-00006 TABLE D-2 Ex # Structure Chemical Name and
Analytical Data D.2.1 ##STR00090## Chemical Name:
4-(methoxycarbonyl)butanamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-
trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-
yl]-3-methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: 1H-NMR
(DMSO-d6): 8.79 (1H, d, J = 2.7 Hz); 8.51 (1H, br); 8.04 (1H, d, J
= 7.9 Hz); 8.3-7.5 (2H, br); 4.31 (1H, m); 4.07 (1H, dd, J = 1.8,
8.6); 3.57 (3H, s); 3.13 (2H, m); 2.55 (1H, m); 2.28 (2H, t, J =
7.7); 2.20 (1H, m); 2.28 (2H, t, J = 7.5); 2.01 (1H, m); 1.85-1.2
(13H, m); 1.23 (3H, s); 1.21 (3H, s); 0.83 (6H, d, J = 6.6); 0.79
(3H, s). D.2.2 ##STR00091## Chemical Name:
4-(1-Butyl-piperidin-4-yl)-butanamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-
trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-
yl]-3-methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: 1H-NMR
(DMSO-d6): 8.78 (1H, d, J = 2.7 Hz); 8.51 (1H, br); 7.97 (1H, d, J
= 8.0 Hz); 8.3-7.5 (2H, br); 4.32 (1H, m); 4.07 (1H, dd, J = 1.8,
8.6); 3.13 (2H, m); 2.78 (2H, br d, J = 11.2); 2.55 (1H, m); 2.19
(3H, m); 2.09 (2H, t, J = 7.5); 2.00 (1H, m); 1.85-1.0 (26H, m);
1.23 (3H, s); 1.21 (3H, s); 0.85 (3H, t, J = 7.9); 0.83 (6H, 2 d, J
= 6.6); 0.79 (3H, s). D.2.3 ##STR00092## Chemical Name:
2-Butoxyacetamide,N-[(1S)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-
methano-1,3,2-benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: 1H-NMR
(DMSO-d6): 8.74 (1H, d, J = 2.8 Hz); 8.51 (1H, br); 8.3-7.5 (2H,
br); 7.61 (1H, d, J = 8.0); 4.39 (1H, m); 4.12 (1H, br d, J = 8.2);
3.85 (2H, s); 3.42 (2H, t, J = 6.4); 3.13 (2H, m); 2.64 (1H, m);
2.20 (1H, m); 2.03 (1H, m); 1.95-1.2 (15H, m); 1.24 (3H, s); 1.21
(3H, s); 0.87 (3H, t, J = 7.3); 0.83 (6H, d, J = 6.6); 0.79 (3H,
s).
[0504] Further compounds prepared according to the above reported
procedure in Example D.2 are reported in Table D-2A The compound of
Example D.2.6, was prepared starting from 2-aminoacetamide,
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-metha-
no-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]-amino]carbonyl]-4-[[imino(ni-
troamino)methyl]-amino]-butyl], hydrochloride salt of Example D.14.
The compounds of example D.2.7 and D.2.8 were prepared from
2-aminoacetamide,
N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-me-
thano-1,3,2-benzodioxaborol-2-yl]-1-methylbutyl]; hydrochloride
salt of Example C.3. The compounds of Examples 2.9 and 2.10 were
prepared from (2S)-2-amino-5-ureidopentanamide,
N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-b-
enzodioxaborol-2-yl]-3-methylbutyl]; hydrochloride salt of Example
C.3
TABLE-US-00007 TABLE D-2A Ex # Structure Chemical Name and
Analytical Data D.2.4 ##STR00093## Chemical Name: 12-[(1,1-
dimethylethoxy)carbonylamino] dodecanamide,N-
[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl]- Analytical Data: 1H NMR
(DMSO-d6) 8.81 (1H, d, J = 2.4); 8.52 (1H, br); 7.98 (1H, d, J =
8.05); 7.85 (2H, v. br); 6.73 (1H, t, J = 5.3); 4.33 (1H, m); 4.07
(1H, d, J = 8.4); 3.14 (2H, m); 2.88 (2H, q, J = 6.6); 2.56 (1H,
m); 2.19 (1H, m); 2.10 (2H, t, J = 7.1); 2.01 (1H, m); 1.83 (1H, t,
J = 5.7); 1.78 (1H, m); 1.73- 1.41 (8H, m); 1.36 (9H, s); 1.33-1.15
(25H, m); 0.84 (6H, d, J = 6.5); 0.80 (3H, s). D.2.5 ##STR00094##
Chemical Name: 4-(methoxycarbonyl)heptanamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-
trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-
yl]-3-methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: 1H-NMR
(DMSO-d6): 8.80 (1H, br s); 8.51 (1H, br); 7.98 (1H, d, J = 8.0
Hz); 8.3-7.5 (2H, br); 4.32 (1H, m); 4.06 (1H, br d, J = 8.4); 3.12
(2H, m); 2.55 (1H, m); 2.26 (2H, t, J = 7.3); 2.18 (1H, m); 2.09
(2H, t, J = 7.1); 2.01 (1H, m); 1.85-1.2 (19H, m); 1.23 (3H, s);
1.21 (3H, s); 0.83 (6H, d, J = 6.6); 0.79 (3H, s). D.2.6
##STR00095## Chemical Name:
2-[2-(2-methoxyethoxy)acetylamino]acetamide,
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl Analytical Data: 1H-NMR
(DMSO-d6): 8.71-8.68 (1H, m); 8.53 (1H, m); 8.15 (1H, d, J = 8.1);
8.10-7.60 (3H, m); 4.40-4.33 (1H, m); 4.13-4.08 (1H, m); 3.92 (2H,
s); 3.82-3.78 (2H, m); 3.64-3.58 (2H, m); 3.52- 3.46 (2H, m); 3.27
(3H, s); 2.62-2.56 (1H, m); 2.26-2.16 (1H, m); 2.08-2.00 (1H, m);
1.85 (1H, t, J = 5.5); 1.82-1.76 (1H, m); 1.72-1.60 (3H, m);
1.59-1.40 (4H, m); 1.32-1.26 (4H, m); 1.25 (3H, s); 1.22 (3H, s);
0.86-0.83 (6H, m); 0.81 (3H, s). D.2.7 ##STR00096## Chemical Name:
Decanamide,N-[1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]methyl]
Analytical Data: 1H-NMR (DMSO-d6): 8.85 (1H, s); 8.11 (1H, t, J =
5.9); 4.07-4.03 (1H, m); 3.83-3.78 (2H, d, J = 6.4); 2.24-2.16 (1H,
m); 2.11 (2H, t, J = 7.40); 2.05-1.95 (1H, m); 1.84 (1h, t, J =
5.6); 1.81-1.75 (1H, m); 1.74-1.60 (2H, m); 1.54-1.45 (2H, m);
1.35-1.30 (1H, d, J = 10.1); 1.28-1.20 (21H, m); 0.90-0.84 (9H, m);
0.81 (3H, s). D.2.8 ##STR00097## Chemical Name:
2-[2-(2-methoxyethoxy) ethoxy]acetamide,N-[1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-
trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-
yl]-3-methylbutyl]amino]carbonyl]methyl] Analytical Data: 1H-NMR
(DMSO-d6): 8.81 (1H, m); 7.97 (1H, t, J = 6.0); 4.09-4.04 (1H, m);
3.93 (2H, s); 3.85 (2H, d, J = 6.0); 3.64-3.57 (2H, m); 3.57-3.50
(4H, m); 3.45-3.40 (2H, m); 3.23 (3H, s); 2.58-2.52 (1H, m);
2.24-2.15 (1H, m); 2.05-1.97 (1H, m); 1.83 (1H, t, J = 5.6);
1.80-1.76 (1H, m); 1.72-1.58 (2H, m); 1.31 (1H, d, J = 10.1);
1.28-1.25 (2H, m); 1.23 (3H, s); 1.21 (3H, s); 0.86-0.82 (6H, m);
0.80 (3H, s). D.2.9 ##STR00098## Chemical Name:
Decanamide,N-[(1S)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-
4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-5-ureidopentyl]- D.2.10 ##STR00099##
Chemical Name: 4-Butylbenzamide,N-[(1S)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-
4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-5-ureidopentyl]-
Example D.3
11-Cyanoundecanamide,
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-metha-
no-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4-[[imino(nit-
roamino)methyl]amino]butyl]-
##STR00100##
[0506] PS-Carbodiimide (N-cyclohexylcarbodiimide-N'-propyloxymethyl
polystyrene, 769 mg, 1 mmol, loading 1.31 mmol/g) and HOAt
(1-Hydroxy-7-azabenzotriazole, 115 mg, 0.85 mmol) were added to a
solution of 11-cyanoundecanoic acid (115 mg, 0.54 mmol) in
dichloromethane (DCM) (9 mL). After stirring for 10 minutes
(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]pentanamide,
N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-b-
enzodioxaborol-2-yl]-3-methylbutyl]-, hydrochloride salt of Example
C.1 (251 mg, 0.50 mmol) and DIPEA (0.128 ml, 0.75 mmol) were added.
The suspension was shaken overnight at room temperature and then
the PS-Carbodiimide was filtered off and washed several times with
DCM (4.times.6 mL).
[0507] The organic phase was passed through a VARIAN CHEM ELUT
cartridge for liquid-liquid extraction pre-conditioned with
saturated aqueous NaHCO.sub.3 and finally washed with DCM (15 mL).
The solvent was evaporated and the crude reaction was purified with
normal-phase ISOLUTE SPE-SI column (DCM 9, MeOH 1) to afford 200 mg
of the desired compound (yield 61%).
[0508] NMR (CDCl.sub.3): 7.53 (s, br, 2H); 7.36 (d, br, J=4.7 Hz,
1H); 6.88 (d, J=8.2 Hz, 1H); 4.46 (m, 1H); 4.15 (dd, J=8.5, 1.9 Hz,
1H); 3.19 (m, 2H); 2.93 (m, 1H); 2.23 (t, J=7.2 Hz, 2H); 2.21 (m,
1H); 2.09 (t, J=7.5, 2H); 2.04 (m, 1H); 1.88 (t, J=5.4 Hz, 1H);
1.77 (m, 1H); 1.69 (m, 1H); 1.64-1.43 (m, 9H); 1.40-1.26 (m, 4H);
1.26 (s, 3H); 1.24-1.12 (m, 16H); 0.80 (d, J=6.6, 3H); 0.79 (d,
J=6.6, 3H); 0.73 (s, 3H).
[0509] LC-MS 659.7, MH+. ESI POS; AQA; spray 4 kV/skimmer:
20V/probe 250 C.
[0510] Further compounds prepared fundamentally in accordance with
the above experimental procedures are reported in Table D-3.
TABLE-US-00008 TABLE D-3 Ex # Structure Chemical Name and
Analytical Data D.3.1 ##STR00101## Chemical Name:
Decanamide,N-[(1S)-1-[[[(1R)-1- [(3aS,4S,6S,7aR)-hexahydro-3a,5,5-
trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
621.5 D.3.2 ##STR00102## Chemical Name:
Naphthalen-1-carboxamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
621.4 D.3.3 ##STR00103## Chemical Name:
2-Phenylacetamide,N-[(1S)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
585.3 D.3.4 ##STR00104## Chemical Name:
1-Phenylcyclopentanecarboxamide,N-
[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
639.4 D.3.5 ##STR00105## Chemical Name:
(2R)-2-Phenylbutanamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
613.4 D.3.6 ##STR00106## Chemical Name:
(2S)-2-Phenylbutanamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
613.4 D.3.7 ##STR00107## Chemical Name:
Dodecanamide,N-[(1S)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
649.5 D.3.8 ##STR00108## Chemical Name:
Octanamide,N-[(1S)-1-[[[(1R)-1- [(3aS,4S,6S,7aR)-hexahydro-3a,5,5-
trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
593.4 D.3.9 ##STR00109## Chemical Name:
Acetamide,N-[(1S)-1-[[[(1R)-1- [(3aS,4S,6S,7aR)-hexahydro-3a,5,5-
trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
509.3 D.3.10 ##STR00110## Chemical Name: 4-(1,1-
Dimethylethyl)cyclohexanecarboxamide,
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
633.5 D.3.11 ##STR00111## Chemical Name:
trans-4-Pentylcyclohexanecarboxamide,
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
647.5 D.3.12 ##STR00112## Chemical Name:
4-Phenylbutanamide,N-[(1S)-1-[[[(1R)-
1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
613.4 D.3.13 ##STR00113## Chemical Name:
2-(3-Methoxyphenyl)acetamide,N-[(1S)-
1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
615.3 D.3.14 ##STR00114## Chemical Name:
4-(1,1-Dimethylethyl)benzamide,N-
[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
627.5 D.3.15 ##STR00115## Chemical Name:
Nonanamide,N-[(1S)-1-[[[(1R)-1- [(3aS,4S,6S,7aR)-hexahydro-3a,5,5-
trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
607.4 D.3.16 ##STR00116## Chemical Name:
(RS)-2-Cyclopentylhexanamide,N-[(1S)-
1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
633.5 D.3.17 ##STR00117## Chemical Name:
Thiophene-2-carboxamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
577.2 D.3.18 ##STR00118## Chemical Name:
2,3-Difluorobenzamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
607.3 D.3.19 ##STR00119## Chemical Name:
2-(2-Iodophenyl)acetamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
711.3 D.3.20 ##STR00120## Chemical Name:
Cyclohexanecarboxamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
577.3 D.3.21 ##STR00121## Chemical Name:
2-(4-Bromophenyl)acetamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
663.2 D.3.22 ##STR00122## Chemical Name:
Benzamide,N-[(1S)-1-[[[(1R)-1- [(3aS,4S,6S,7aR)-hexahydro-3a,5,5-
trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
571.3 D.3.23 ##STR00123## Chemical Name:
2-Methylbenzamide,N-[(1S)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
585.3 D.3.24 ##STR00124## Chemical Name:
4-Bromobenzamide,N-[(1S)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
649.3 D.3.25 ##STR00125## Chemical Name:
(2S)-2-Phenylpropanamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
599.3 D.3.26 ##STR00126## Chemical Name:
(E)-2-Methyl-3-phenyl-acrylamide,N-
[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
611.4 D.3.27 ##STR00127## Chemical Name:
2-[(Naphthalen-2-yl)oxy]acetamide,N-
[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
651.4 D.3.28 ##STR00128## Chemical Name:
2,2-Dimethylbutanamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
565.4 D.3.29 ##STR00129## Chemical Name:
2-(2-Chlorophenyl)acetamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
619.3 D.3.30 ##STR00130## Chemical Name:
5-Methylthiophene-2-carboxamide,N-
[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
591.3 D.3.31 ##STR00131## Chemical Name:
cis-3-(2-Methoxyphenyl)acrylamide,N-
[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
627.4 D.3.32 ##STR00132## Chemical Name:
(2-Methylphenoxy)acetamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
615.4 D.3.33 ##STR00133## Chemical Name:
2-(2,5-Dimethylphenyl)acetamide,N-
[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
613.4 D.3.34 ##STR00134## Chemical Name:
trans-3-(2-Bromophenyl)acrylamide,N-
[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
675.3 D.3.35 ##STR00135## Chemical Name:
4-Isopropylbenzamide,N-[(1S)-1-[[[(1R)-
1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
613.4 D.3.36 ##STR00136## Chemical Name:
4-(4-methylphenyl)butanamide,N-[(1S)-
1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
627.4 D.3.37 ##STR00137## Chemical Name:
2-(2-Naphthylsulfanyl)acetamide,N-
[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
667.3 D.3.38 ##STR00138## Chemical Name:
5-Methylhexanamide,N-[(1S)-1-[[[(1R)-
1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
579.4 D.3.39 ##STR00139## Chemical Name:
3-Thiophen-2-yl-propanamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
605.4 D.3.40 ##STR00140## Chemical Name:
2,4-Dimethylthiazole-5-carboxamide,N-
[(1S)-1-[[[(1R)-1-[(3a,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
606.4 D.3.41 ##STR00141## Chemical Name:
Furan-3-carboxamide,N-[(1S)-1-[[[(1R)-
1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
561.3 D.3.42 ##STR00142## Chemical Name:
(2R)-2-Phenylpropanamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4- [immo(nitroamino)methyl]amino]butyl]
Analytical Data: MS: MH+ 599.4 D.3.43 ##STR00143## Chemical Name:
2-Cycloheptylacetamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5,trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
605.4 D.3.44 ##STR00144## Chemical Name:
1-Methylcyclopropanecarboxamide,N-
[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
549.3 D.3.45 ##STR00145## Chemical Name:
1-Methyl-cyclohexanecarboxamide,N-
[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl]
Analytical Data: MS: MH+ 591.3 D.3.46 ##STR00146## Chemical Name:
2-[(1S,2R,5S)-2-isopropyl-5- methylcyclohexyl]oxyacetamide,N-[(1S)-
1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
663.3 D.3.47 ##STR00147## Chemical Name:
(E)-2-Butenamide,N-[(1S)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]ammo]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
535.6 D.3.48 ##STR00148## Chemical Name:
3-Methylbutanamide,N-[(1S)-1-[[[(1R)-
1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(mtroamino)methyl]amino]butyl] Analytical Data: MS: MH+
551.3 D.3.49 ##STR00149## Chemical Name:
3-Phenylpropanamide,N-[(1S)-1-[[[(1R)-
1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
599.3 D.3.50 ##STR00150## Chemical Name:
4-(4-Methoxyphenyl)-butanamide,N-
[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
643.4 D.3.51 ##STR00151## Chemical Name:
Thiophene-3-carboxamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
577.2 D.3.52 ##STR00152## Chemical Name:
2-Thiophen-3-yl-acetamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylhutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
591.4 D.3.53 ##STR00153## Chemical Name: (E)-Penta-2,4-dienoic acid
amide,N- [(1S)-l-[[[(1R)-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
547.3 D.3.54 ##STR00154## Chemical Name:
2-(4-Isopropylphenoxy)acetamide,N-
[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
643.4 D.3.55 ##STR00155## Chemical Name:
2-(4-Ethylphenoxy)acetamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
629.4 D.3.56 ##STR00156## Chemical Name: (E)-2-Methylhex-2-enoic
acid amide,N- [(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroammo)methyl]amino]butyl] Analytical Data: MS: MH+
577.2 D.3.57 ##STR00157## Chemical Name:
3-(3-Methylphenyl)acrylamide,N-[(1S)-
1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
611.4 D.3.58 ##STR00158## Chemical Name:
2-Adamantan-1-ylacetamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
643.3 D.3.59 ##STR00159## Chemical Name:
(RS)-2-Cyclopent-2-enylacetamide,N-
[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[immo(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+ 575.3
D.3.60 ##STR00160## Chemical Name:
4-Diethylaminobenzamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
642.4 D.3.61 ##STR00161## Chemical Name:
(RS)-2-Methylbutanamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
551.3 D.3.62 ##STR00162## Chemical Name:
3-(4-Methylphenyl)acrylamide,N-[(1S)-
1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
611.4 D.3.63 ##STR00163## Chemical Name: Hexa-2,4-dienoic acid
amide,N-[(1S)-1- [[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
561.5 D.3.64 ##STR00164## Chemical Name:
4-Pyrrol-1-yl-benzamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
636.3 D.3.65 ##STR00165## Chemical Name:
(E)-3-Thiophen-3-yl-acrylamide,N-[(1S)-
1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
603.3 D.3.66 ##STR00166## Chemical Name:
Hept-2-enamide,N-[(1S)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
577.3 D.3.67 ##STR00167## Chemical Name:
2-(3,4-Dimethylphenoxy)acetamide,N-
[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
629.3 D.3.68 ##STR00168## Chemical Name:
Dec-9-enamide,N-[(1S)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
619.3 D.3.69 ##STR00169## Chemical Name: (E)-Undec-2-enoic acid
amide,N-[(1S)-1- [[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
633.4 D.3.70 ##STR00170## Chemical Name: (E)-Dec-3-enoic acid
amide,N-[(1S)-1- [[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
619.4 D.3.71 ##STR00171## Chemical Name:
2,2-Dimethyl-3-(2-methylpropenyl)-
cyclopropanecarboxamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
616.9 D.3.72 ##STR00172## Chemical Name:
2-Methylcyclohexanecarboxamide,N-
[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
591.4 D.3.73 ##STR00173## Chemical Name:
5-Cyclohexylpentanamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
633.5 D.3.74 ##STR00174## Chemical Name:
3-Methoxycyclohexanecarboxamide,N-
[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
607.3 D.3.75 ##STR00175## Chemical Name:
(3R)-3,7-Dimethyl-oct-6-enoic acid amide,N-[(1S)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
619.4 D.3.76 ##STR00176## Chemical Name: 3-[(4-
methylbenzyl)sulfanyl]propanamide,N-
[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
659.3 D.3.77 ##STR00177## Chemical Name:
(3S)-3,7-Dimethyl-oct-6-enoic acid amide,N-[(1S)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
619.4 D.3.78 ##STR00178## Chemical Name:
(RS)-4-Ethyloctanamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
621.4 D.3.79 ##STR00179## Chemical Name:
5-Fluoro-2-methoxybenzamide,N-[(1S)-
1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
619.2 D.3.80 ##STR00180## Chemical Name:
2-(4-Bromophenoxy)-acetamide,N-[(1S)-
1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
679.6 D.3.81 ##STR00181## Chemical Name:
2-(1-Methyl-1H-indol-3-yl)acetamide,N-
[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
638.3 D.3.82 ##STR00182## Chemical Name:
Hexahydro-2,5-methanopentalene-
3a(1H)-carboxamide,N-[(1S)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
615.2 D.3.83 ##STR00183## Chemical Name:
Bicyclo[2.2.1]heptane-2-carboxamide,N-
[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
589.2 D.3.84 ##STR00184## Chemical Name:
(RS)-2-(4-Chlorophenyl)propionamide,
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
633.6 D.3.85 ##STR00185## Chemical Name:
(2S)-2-methylbutanamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
551.8 D.3.86 ##STR00186## Chemical Name:
(4RS)-1-[(1,1-dimethylethoxy)carbonyl]-
piperidine-4-carboxamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
678.4 D.3.87 ##STR00187## Chemical Name:
(RS)-4-Methyloctanamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
607.3 D.3.88 ##STR00188## Chemical Name:
2-Fluoro-5-methylbenzamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
603.2 D.3.89 ##STR00189## Chemical Name:
2-(Bicyclo[2.2.1]hept-2-yl)acetamide,N-
[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
603.8 D.3.90 ##STR00190## Chemical Name:
Cyclopropanecarboxamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
535.3 D.3.91 ##STR00191## Chemical Name:
4-Ethoxybenzamide,N-[(1S)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
615.2 D.3.92 ##STR00192## Chemical Name:
(E)-3-(4-Bromophenyl)acrylamide,N-
[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
675.1 D.3.93 ##STR00193## Chemical Name:
(2S)-2-(6-Methoxynaphthalen-2-yl)- propanamide,N-[(1S)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
679.3 D.3.94 ##STR00194## Chemical Name:
3-Fluoro-4-methoxybenzamide,N-[(1S)-
1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
619.5 D.3.95 ##STR00195## Chemical Name:
4-Fluoro-3-methylbenzamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
603.2 D.3.96 ##STR00196## Chemical Name: Non-2-enoic acid
amide,N-[(1S)-1- [[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
605.3 D.3.97 ##STR00197## Chemical Name:
(E)-3-(Naphthalen-2-yl)acrylamide,N-
[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
647.3 D.3.98 ##STR00198## Chemical Name:
Quinoline-2-carboxamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
622.3 D.3.99 ##STR00199## Chemical Name: 1-(4-Methoxyphenyl)-
cyclopropanecarboxamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
641.4 D.3.101 ##STR00200## Chemical Name:
3-Butenamide,N-[(1S)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
535.0 D.3.102 ##STR00201## Chemical Name:
Tetradecanamide,N-[(1S)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
677.3 D.3.103 ##STR00202## Chemical Name:
3-(1H-Indol-3-yl)-propanamide,N-[(1S)-
1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
638.2 D.3.104 ##STR00203## Chemical Name:
4-Phenoxybutanamide,N-[(1S)-1-[[[(1R)-
[[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
628.9 D.3.105 ##STR00204## Chemical Name:
5-Oxo-5-phenyl-pentanamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-l,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
641.1 D.3.106 ##STR00205## Chemical Name:
(2RS)-1-((1,1-dimethylethoxy)carbonyl)-
piperidine-2-carboxamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
678.2 D.3.107 ##STR00206## Chemical Name:
Pyridine-2-carboxamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
572.1 D.3.108 ##STR00207## Chemical Name:
Pyridine-3-carboxamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
572.1 D.3.109 ##STR00208## Chemical Name:
Pyridine-4-carboxamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
572.5 D.3.110 ##STR00209## Chemical Name:
(2S)-1-((1,1-dimethylethoxy)carbonyl)-
piperidine-2-carboxamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
678.1 D.3.111 ##STR00210## Chemical Name:
(2R)-1-((1,1-dimethylethoxy)carbonyl)-
piperidine-2-carboxamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
678.2 D.3.112 ##STR00211## Chemical Name:
3,3-Dimethyl-butanamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
565.0 D.3.113 ##STR00212## Chemical Name:
4-[(Phenylamino)carbonyl]butanamide,
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
656.2 D.3.114 ##STR00213## Chemical Name:
2,2-Dimethylpentanamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
579.2 D.3.115 ##STR00214## Chemical Name:
5-Thiophen-2-yl-pentanamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
633.2 D.3.116 ##STR00215## Chemical Name:
(3RS)-1-((1,1-dimethylethoxy)carbonyl)-
piperidine-3-carboxamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
678.0 D.3.117 ##STR00216## Chemical Name:
8-Phenyl-octanamide,N-[(1S)-1-[[[(1R)-
1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
669.1 D.3.118 ##STR00217## Chemical Name: 3-[[(1,1-
dimethylethoxy)carbonyl]amino] propanamide,N-[(1S)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
638.2 D.3.119 ##STR00218## Chemical Name:
Tridecanamide,N-[(1S)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
663.3 D.3.120 ##STR00219## Chemical Name:
Succinamide,N-[(1S)-1-[[[(1R)-1- [(3aS,4S,6S,7aR)-hexahydro-3a,5,5-
trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
566.1 D.3.121 ##STR00220## Chemical Name:
Pentanamide,N-[(1S)-1-[[[(1R)-1- [(3aS,4S,6S,7aR)-hexahydro-3a,5,5-
trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
551.2 D.3.122 ##STR00221## Chemical Name: [[[(9H-fluoren-9-
yl)methoxy]carbonyl]amino]butanamide,
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
775.3 D.3.123 ##STR00222## Chemical Name:
2-(Dimethylamino)acetamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
552.5 D.3.124 ##STR00223## Chemical Name:
5-(4-Fluorophenyl)-pentanamide,N-
[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
645.2 D.3.125 ##STR00224## Chemical Name:
8-Oxo-8-phenyloctanamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-l,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
683.1 D.3.126 ##STR00225## Chemical Name:
4-(Thiophen-2-yl)butanamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
619.0 D.3.127 ##STR00226## Chemical Name:
5-Oxo-5-(thiophen-2-yl)pentanamide,N-
[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: MH+
647.1 D.3.128 ##STR00227## Chemical Name:
2-(3-Chlorophenyl)acetamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
619.1 D.3.129 ##STR00228## Chemical Name:
Undecanamide,N-[(1S)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
635.2 D.3.130 ##STR00229## Chemical Name:
4-Heptylbenzamide,N-[(1S)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
669.6 D.3.131 ##STR00230## Chemical Name:
6-Phenylhexanamide,N-[(1S)-1-[[[(1R)-
1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
641.5 D.3.132 ##STR00231## Chemical Name:
5-Phenylpentanamide,N-[(1S)-1-[[[(1R)-
1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
627.5 D.3.133 ##STR00232## Chemical Name:
10-Hydroxydecanamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
637.7
D.3.134 ##STR00233## Chemical Name: 5-Oxo-5-(4-phenylpiperazin-1-
yl)pentanamide,N-[(1S)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
725.4 D.3.135 ##STR00234## Chemical Name:
2-(1H-Tetrazol-5-yl)acetamide,N-[(1S)-
1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
577.0 D.3.136 ##STR00235## Chemical Name:
2-(Tetrazol-1-yl)acetamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
576.9 D.3.137 ##STR00236## Chemical Name:
2-(Pyrimidin-2-ylsulfanyl)acetamide,N-
[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
618.9 D.3.138 ##STR00237## Chemical Name:
3-Methylsulfanylpropanamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
569.4 D.3.139 ##STR00238## Chemical Name:
3-(Naphthalen-2-ylsulfanyl)- propanamide,N-[(1S)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
681.5 D.3.140 ##STR00239## Chemical Name:
2-[(Phenylmethyl)sulfanyl]acetamide,N-
[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
631.5 D.3.141 ##STR00240## Chemical Name:
6-Oxoheptanamide,N-[(1S)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
593.5 D.3.142 ##STR00241## Chemical Name:
4-(4-Methanesulfonylphenyl)-4- oxobutanamide,N-[(1S)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
705.0 D.3.143 ##STR00242## Chemical Name:
(2S)-1-Acetylpyrrolidine-2-carboxamide,
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
605.9 D.3.144 ##STR00243## Chemical Name:
3-Hydroxy-2,2-dimethylpropanamide,N-
[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
566.9 D.3.145 ##STR00244## Chemical Name:
2-Ethylsulfanylacetamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
569.8 D.3.146 ##STR00245## Chemical Name:
3-Ureidopropanamide,N-[(1S)-1-[[[(1R)-
1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
581.5 D.3.147 ##STR00246## Chemical Name:
3-Methoxypropanamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
552.9 D.3.148 ##STR00247## Chemical Name:
2-Methylsulfanylacetamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
555.6 D.3.149 ##STR00248## Chemical Name:
3H-Imidazole-4-carboxamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
561.0 D.3.150 ##STR00249## Chemical Name:
7-Oxo-octanamide,N-[(1S)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
607.1 D.3.151 ##STR00250## Chemical Name:
(E)-3-(Imidazol-4-yl)acrylamide,N-[(1S)-
1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
587.4 D.3.152 ##STR00251## Chemical Name:
(RS)-Tetrahydrofuran-3-carboxamide,N-
[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
565.3 D.3.153 ##STR00252## Chemical Name:
(E)-3-(2-Methoxyphenyl)acrylamide,N-
[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
627.7 D.3.154 ##STR00253## Chemical Name:
2-Ethoxyacetamide,N-[(1S)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
553.0 D.3.155 ##STR00254## Chemical Name:
3-Furan-2-yl-propanamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
589.5 D.3.156 ##STR00255## Chemical Name:
3-(Benzenesulfonyl)propanamide,N-
[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[immo(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
663.0 D.3.157 ##STR00256## Chemical Name:
4-Sulfamoylbutanamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
615.8 D.3.158 ##STR00257## Chemical Name:
(4S)-2-Oxo-1,3-thiazolidine-4- carboxamide,N-[(1S)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[immo(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
595.8 D.3.159 ##STR00258## Chemical Name:
(2R)-1-Acetylpyrrolidine-2-carboxamide,
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
605.9 D.3.160 ##STR00259## Chemical Name:
3-[(Acetylamino)methylsulfanyl]- propanamide,N-[(1S)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
626.0 D.3.161 ##STR00260## Chemical Name:
6-(Acetylsulfanyl)hexanamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
638.9 D.3.162 ##STR00261## Chemical Name:
(Thiophene-2-sulfonyl)acetamide,N-
[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
655.0 D.3.163 ##STR00262## Chemical Name:
4-(Acetylamino)butanamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
593.7 D.3.164 ##STR00263## Chemical Name:
(2Z)-3-(Propylaminocarbonyl)-2- propenamide,N-[(1S)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
606.1 D.3.165 ##STR00264## Chemical Name:
3-(Octylsulfonyl)propanamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
699.29 D.3.166 ##STR00265## Chemical Name:
3-(Octylsulfanyl)propanamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
667.35 D.3.167 ##STR00266## Chemical Name:
2,2-Dimethylhexanamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
593.65 D.3.168 ##STR00267## Chemical Name:
6-Hydroxyhexanamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
581.16 D.3.169 ##STR00268## Chemical Name:
4-Oxopentanamide,N-[(1S)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
565.60 D.3.170 ##STR00269## Chemical Name:
5-Oxohexanamide,N-[(1S)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
579.17 D.3.171 ##STR00270## Chemical Name:
Benzothiazole-6-carboxamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4- [immo(nitroamino)methyl]amino]butyl]
Analytical Data: MS: [MH]+ 628.70 D.3.172 ##STR00271## Chemical
Name: 3-(Octyloxy)propanamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
651.33 D.3.173 ##STR00272## Chemical Name:
2-(2-Oxo-pyrrolidin-1-yl)-acetamide,N-
[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
592.75 D.3.174 ##STR00273## Chemical Name:
Benzamide,N-[(1S,2R)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-2-
hydroxypropyl] Analytical Data: MS: [MH]+ 471.47 D.3.175
##STR00274## Chemical Name: 2-[2-(2-
Methoxyethoxy)ethoxy]acetamide,N-
[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-2-
hydroxypropyl] Analytical Data: MS: [MH]+ 527.12 D.3.176
##STR00275## Chemical Name: 4-Phenylbutanamide,N-[(1S,2R)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-l53.2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-2- hydroxypropyl]
Analytical Data: MS: [MH]+ 513.10 D.3.177 ##STR00276## Chemical
Name: (4-Methylphenoxy)acetamide,N-
[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-2-
hydroxypropyl] Analytical Data: MS: [MH]+ 515.57 D.3.178
##STR00277## Chemical Name: Hexanamide,N-[(1S,2R)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-2-
hydroxypropyl] Analytical Data: MS: [MH]+ 465.40 D.3.179
##STR00278## Chemical Name: 4-Butylbenzamide,N-[(1S,2R)-1-[[[(1R)-
1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-2-
hydroxypropyl] Analytical Data: MS: [MH]+ 527.16 D.3.180
##STR00279## Chemical Name: Naphthalene-2-carboxamide,N-[(1S,2R)-
1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-2- hydroxypropyl] Analytical Data: MS:
[MH]+ 521.14 D.3.181 ##STR00280## Chemical Name:
Hexanamide,N-[(1S)-1-[[[(1R)-1- [(3aS,4S,6S,7aR)-hexahydro-3a,5,5-
trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4- [immo(nitroamino)methyl]amino]butyl]
Analytical Data: MS: [MH]+ 565.33 D.3.182 ##STR00281## Chemical
Name: 2-(4-Methylbenzenesulfonyl)acetamide,
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
663.30 D.3.183 ##STR00282## Chemical Name:
Heptanamide,N-[(1S)-1-[[[(1R)-1- [(3aS,4S,6S,7aR)-hexahydro-3a,5,5-
trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
579.34 D.3.184 ##STR00283## Chemical Name:
11-(Carbamoyl)undecanamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
678.44 D.3.185 ##STR00284## Chemical Name:
2-(Benzenesulfonyl)acetamide,N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl] Analytical Data: MS: [MH]+
649.28
[0511] Further compounds prepared according to the above Example
D.3 are reported in Table D-3A.
TABLE-US-00009 TABLE D-3A Ex # Structure Chemical Name and
Analytical Data D.3.186 ##STR00285## Chemical Name:
9-Cyanononamide, N-[(1S)-1-[[[(1R)-
1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino] butyl] Analytical Data: MS: MH+
632.5 D.3.187 ##STR00286## Chemical Name: 11-Cyanoundecanamide,
N-[(1S)-1- [[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]
butyl] Analytical Data: MS: MH+ 659.7; 1H-NMR (CDCl3): 7.53 (s, br,
2H); 7.36 (d, br, J = 4.7 Hz, 1H); 6.88 (d, J = 8.2 Hz, 1H); 4.46
(m, 1H); 4.15 (dd, J = 8.5, 1.9 Hz, 1H); 3.19 (m, 2H); 2.93 (m,
1H); 2.23 (t, J = 7.2 Hz, 2H); 2.21 (m, 1H); 2.09 (t, J = 7.5, 2H);
2.04 (m, 1H); 1.88 (t, J = 5.4 Hz, 1H); 1.77 (m, 1H); 1.69 (m, 1H);
1.64-1.43 (m, 9H); 1.40-1.26 (m, 4H); 1.26 (s, 3H); 1.24-1.12 (m,
16H); 0.80 (d, J = 6.6, 3H); 0.79 (d, J = 6.6, 3H); 0.73 (s, 3H).
D.3.188 ##STR00287## Chemical Name: 6-(Acetylamino)hexanamide,
N-[(1S)- 1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6- methano-1,3,2-benzodioxaborol-2-
yl]-3-methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino] butyl] Analytical Data: MS: [MH]+
622.3 D.3.189 ##STR00288## Chemical Name:
12-(1,3-Dioxo-1,3-dihydro-isoindol- 2-yl)-dodecanamide, N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)- hexahydro-3a,5,5-
trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]
butyl] Analytical Data: MS: [MH]+ 794.42 D.3.190 ##STR00289##
Chemical Name: 3-[4-(2-Propyl)phenyl]propanamide,
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6- methano-1,3,2-benzodioxaborol-2-
yl]-3-methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino] butyl] Analytical Data: MS: [M]H+
641.5 D.3.191 ##STR00290## Chemical Name:
3-[4-(Ethyl)phenyl]propanamide,
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6- methano-1,3,2-benzodioxaborol-2-
yl]-3-methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino] butyl] Analytical Data: MS: [M]H+
627.7 D.3.192 ##STR00291## Chemical Name: 6-hydroxyhexanamide,
N-[(1S)-1- [[[(1R)-1-[(3aS,4S,6S,7aR)- hexahydro-3a,5,5-
trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]
butyl] Analytical Data: MS: [M]H+ 581.5
Example D.4
Naphthalene-2-sulfonamide,
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-metha-
no-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4-[[imino(nit-
roamino)methyl]amino]butyl]-
##STR00292##
[0513] To a solution of
(2S)-2-amino-5-[[imino(nitroamino)methyl]-amino]-pentanamide,
N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-b-
enzodioxaborol-2-yl]-3-methylbutyl]-, hydrochloride salt of Example
C.1 (70 mg, 0.14 mmol) in DCM (4 mL), TEA (0.04 mL, 0.31 mmol) and
naphthalene-2-sulfonyl chloride (35.1 mg, 0.16 mmol) were added at
room temperature. After stirring overnight a second portion of TEA
(0.04 mL, 0.31 mmol) and naphthalene-2-sulfonyl chloride (35.1 mg,
0.16 mmol) was added and the reaction was allowed to stir for a
further night. The reaction mixture was then washed with saturated
aqueous K.sub.2CO.sub.3 and the separated organic phase was
concentrated to dryness. The reaction crude was purified on SPE-SI
normal phase cartridge to afford the title compound (64 mg, yield
70%).
[0514] NMR (CDCl.sub.3): 8.42 (s, br, 1H); 7.96 (dd, J=7.5, 2.2 Hz,
1H); 7.95 (d, J=8.5 Hz, 1H); 7.89 (d, br, J=7.9 Hz, 1H); 7.81 (dd,
J=8.8, 1.9 Hz, 1H); 7.68-7.57 (m, 2H); 7.23 (s br, 2H); 6.23 (s br,
1H); 6.03 (d, J=8.5 Hz, 1H); 4.19 (dd, J=9.1, 2.2 Hz, 1H); 3.92 (s,
br, 1H); 3.31 (m, 2H); 2.97 (m, 1H); 2.26 (m, 1H); 2.12 (m, 1H);
1.93 (t, J=5.7 Hz, 1H); 1.90-1.68 (m, 6H); 1.30 (s, 3H); 1.28 (m,
1H); 1.25 (s, 3H); 1.06 (m, 4H); 0.79 (s, 3H); 0.58 (d, J=9.4 Hz,
3H); 0.56 (d, J=9.4 Hz, 3H).
[0515] LC-MS 657.3, MH+, ESI POS; AQA; spray 4 kV/skimmer: 20
V/probe 250 C.
[0516] Further compounds prepared fundamentally in accordance with
the above experimental procedures are reported in Table D-4.
TABLE-US-00010 TABLE D-4 Ex # Structure Chemical Name and
Analytical Data D.4.1 ##STR00293## Chemical Name:
Naphthalene-1-sulfonamide, N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]
butyl] Analytical Data: MS: MH+ 657.3 D.4.2 ##STR00294## Chemical
Name: Naphthalene-2-sulfonamide, N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]
butyl] Analytical Data: MS: MH+ 657.3; 1H-NMR (CDCl3): 8.42 (s, br,
1H); 7.96 (dd, J = 7.5, 2.2 Hz, 1H); 7.95 (d, J = 8.5 Hz, 1H); 7.89
(d, br, J = 7.9 Hz, 1H); 7.81 (dd, J = 8.8, 1.9 Hz, 1H); 7.68-7.57
(m, 2H); 7.23 (s br, 2H); 6.23 (s br, 1H); 6.03 (d, J = 8.5 Hz,
1H); 4.19 (dd, J = 9.1, 2.2 Hz, 1H); 3.92 (s, br, 1H); 3.31 (m,
2H); 2.97 (m, 1H); 2.26 (m, 1H); 2.12 (m, 1H); 1.93 (t, J = 5.7 Hz,
1H); 1.90-1.68 (m, 6H); 1.30 (s, 3H); 1.28 (m, 1H); 1.25 (s, 3H);
1.06 (m, 4H); 0.79 (s, 3H); 0.58 (d, J = 9.4 Hz, 3H); 0.56 (d, J =
9.4 Hz, 3H). D.4.3 ##STR00295## Chemical Name:
Decane-1-sulfonamide, N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]
amino]butyl] Analytical Data: MS: MH+ 671.4 D.4.4 ##STR00296##
Chemical Name: Octanesulfonamide, N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]
amino]butyl] Analytical Data: MS: MH+ 643.4 D.4.5 ##STR00297##
Chemical Name: Benzenesulfonamide, N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]
amino]butyl] Analytical Data: MS: MH+ 607.3 D.4.6 ##STR00298##
Chemical Name: 4-Butoxyenzenesulfonamide, N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]
amino]butyl] Analytical Data: MS: [M + H]+ 679.5 D.4.7 ##STR00299##
Chemical Name: 4-Butyl-benzenesulfonamide, N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro- 3a,5,5-trimethyl-4,6-
methano-1,3,2-benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]
butyl] Analytical Data: MS: [M]H+ 663.5 D.4.8 ##STR00300## Chemical
Name: 4-Pentyl-benzenesulfonamide, N-[(1S)-
1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]
amino]butyl] Analytical Data: MS: [M]H+ 677.3
Example D.4.9
Naphthalene-2-sulfonamide,
N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-me-
thano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxyp-
ropyl]
##STR00301##
[0518] Naphthalene-2-sulfonyl chloride (144 mg, 0.637 mmol) was
added to a solution of (2S)-amino-(3R)-hydroxy-butyric amide,
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-metha-
no-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]-carbonyl]hydrochloride
salt, of Example C.3, and NMM (0.175 ml, 1.59 mmol) in anhydrous
dichloromethane, while stirring at 0.degree. C. under nitrogen.
After 6 hours the mixture was allowed to warm to room temperature
and stirred overnight. A 10% solution of NaHCO.sub.3 (10 ml) was
added and the layers were separated. The aqueous phase was further
extracted with dichloromethane (5 ml). The organic phases were
washed with a 20% solution of NaH.sub.2PO.sub.4, dried over sodium
sulfate and concentrated. The residue was purified by column
chromatography (Silica gel, 25 g) eluting with a 1:1 (v/v) mixture
of hexane and ethyl acetate. The product was obtained as a white
glassy solid (219 mg, 74% yield) but still containing some
pinanediol. A sample of that product (160 mg) was triturated with a
mixture of diethyl ether (3 ml) and hexane (3 ml) affording the
pure product as a white solid (80 mg, 27% yield). M.p.
147-149.degree. C.
[0519] .sup.1H NMR (DMSO-d6): 8.40 (1H, s); 8.28-8.22 (1H, m); 8.11
(1H, d, J=7.7); 8.05 (1H, d, J=8.7); 8.01 (1H, d, J=7.8); 7.81 (1H,
dd, J=8.7, 1.7); 7.75 (1H, s br.); 7.72-7.61 (2H, m); 4.84 (1H, s
br.); 4.03 (1H, dd, J=8.5, 1.7); 3.82-3.72 (2H, m); 2.41-2.33 (1H,
m); 2.20-2.10 (1H, m); 2.02-1.93 (1H, m); 1.82-1.72 (2H, m);
1.58-1.50 (1H, m); 1.36-1.24 (1H, m); 1.20 (3H, s); 1.18 (3H, s);
0.99 (3H, d, J=6.1); 0.94-0.82 (2H, m); 0.77 (3H, s); 0.63 (3H, d,
J=7.1); 0.61 (3H, d, J=7.1).
Example D.5
(2S)-4-[[imino(nitroamino)methyl]amino]-2-[(2-naphthylmethyl)-amino]-penta-
namide,
N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano--
1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]
##STR00302##
[0521] A solution of
(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]pentanamide,
N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-b-
enzodioxaborol-2-yl]-3-methylbutyl]-, hydrochloride salt of Example
C.1 (88 mg, 0.175 mmol) in MeOH (4 mL) was passed through a ISOLUTE
PSA cartridge in order to obtain the starting material as a free
base. To a solution of the free base in MeOH (4 mL),
2-naphtaldehyde (45 mg, 0.28 mmol) and NaCNBH.sub.3 (18 mg, 0.28
mmol) were added at room temperature; AcOH was added until the pH
of the solution was 4-5. The reaction mixture was stirred
overnight, then H.sub.2O (1 mL) was added and the resulting
solution was concentrated; the residue, dissolved in AcOEt, was
washed with brine and the organic phase was concentrated to
dryness. Purification by silica gel flash chromatography
(DCM/MeOH/NH.sub.4OH, 97.5/2.5/0.25) of the reaction crude,
afforded the desired compound (30 mg, yield 28%).
[0522] NMR (CDCl.sub.3+D.sub.2O): 7.81 (m, 3H); 7.71 (s, br, 1H);
7.52-7.38 (m, 3H); 4.66 (s, br, 1H); 4.27 (dd, J=8.8, 1.9 Hz, 1H);
3.91 and 3.83 (ABq, 2H); 3.39-3.11 (m, 3H); 2.30 (m, 1H); 2.13 (m,
1H); 1.98-1.45 (m, 8H); 1.45 (m, 2H); 1.38 (s, 3H); 1.23 (s, 3H);
1.22 (m, 1H); 0.91 (d, J=6.3 Hz, 6H); 0.81 (s, 3H).
[0523] LC-MS 607.1, MH+. ESI POS; AQA; spray 4 kV/skimmer: 20
V/probe 250 C.
[0524] Further compounds prepared fundamentally in accordance with
the above experimental procedures are reported in Table D-5.
TABLE-US-00011 TABLE D-5 Ex # Structure Chemical Name and
Analytical Data D.5.1 ##STR00303## Chemical Name:
(2S)-4-[[imino(nitroamino)methyl]amino]-2-[(2-
naphthylmethyl)-amino]-pentanamide, N-[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-
methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl] Analytical
Data: MS: MH+ 607.1; 1H-NMR (CDCl3 + D2O): 7.81 (m, 3H); 7.71 (s,
br, 1H); 7.52-7.38 (m, 3H); 4.66 (s, br, 1H); 4.27 (dd, J = 8.8,
1.9 Hz, 1H); 3.91 and 3.83 (ABq, 2H); 3.39-3.11 (m, 3H); 2.30 (m,
1H); 2.13 (m, 1H); 1.98-1.45 (m, 8H); 1.45 (m, 2H); 1.38 (s, 3H);
1.23 (s, 3H); 1.22 (m, 1H); 0.91 (d, J = 6.3 Hz, 6H); 0.81 (s, 3H).
D.5.2 ##STR00304## Chemical Name:
(2S)-4-[[imino(nitroamino)methyl]amino]-2-[(1-
naphthylmethyl)-amino]-pentanamide, N-[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-
methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl] Analytical
Data: MS: MH+ 607.2 D.5.3 ##STR00305## Chemical Name:
(2S)-4-[[imino(nitroamino)methyl]amino]-2-
[undecylamino]-pentanamide, N-[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-
methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl] Analytical
Data: MS: MH+ 621.2 D.5.4 ##STR00306## Chemical Name:
(2S)-4-[[imino(nitroamino)methyl]amino]-2-
[(phenylmethyl)amino]-pentanamide, N-[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-
methano-1,3,2-benzodioxaborol-2-yl]-3- methylbutyl] Analytical
Data: MS: MH+ 557.2
Example D.6
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methan-
o-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4-[[imino(nitr-
oamino)methyl]amino]butyl]-N'-(1-naphthyl)urea
##STR00307##
[0526] To a solution of
(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-pentanamide,
N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-b-
enzodioxaborol-2-yl]-3-methylbutyl]-, hydrochloride salt of Example
C.1 (50 mg, 0.10 mmol) in CH.sub.3CN (4 mL), TEA (0.014 mL, 0.10
mmol) and naphthalene-1-isocyanate (0.014 mL, 0.10 mmol) were added
at room temperature. The reaction mixture was stirred for 4 hours
and then concentrated to dryness. The residue, dissolved in DCM,
was washed with H.sub.2O: the organic layer was separated and the
solvent removed under vacuum. Purification by silica gel flash
chromatography (DCM 95, MeOH 5) gave the title compound as a white
powder (60 mg, yield 94%).
[0527] NMR (CDCl.sub.3): 8.08 (s, br, 1H); 7.98 (m, 1H); 7.79 (m,
2H); 7.57 (d, J=8.2 Hz, 1H); 7.51-7.35 (m, 4H); 7.36 (d, J=7.5 Hz,
1H); 7.17 (s, br, 1H); 6.67 (d, br, J=6.6 Hz, 1H); 4.49 (m, 1H);
4.20 (dd, J=8.5, 1.9 Hz, 1H); 3.39 (m, 1H); 3.20 (m, 1H); 3.04 (m,
1H); 2.26 (m, 1H); 2.08 (m, 2H); 1.93 (t, J=5.6 Hz, 1H); 1.89-1.55
(m, 7H); 1.39 (m, 1H); 1.32 (s, 3H); 1.31 (m, 1H); 1.21 (s, 3H);
1.20 (m, 1H); 0.85 (d, J=6.0 Hz, 6H); 0.79 (s, 3H).
[0528] LC-MS 636.3, MH+. ESI POS; AQA; spray 4 kV/skimmer: 20
V/probe 250.degree. C.
[0529] Further compounds prepared fundamentally in accordance with
the above experimental procedures are reported in Table D-6.
TABLE-US-00012 TABLE D-6 Ex # Structure Chemical Name and
Analytical Data D.6.1 ##STR00308## Chemical Name:
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino] butyl]-N'-(2-naphthyl) urea
Analytical Data: MS: MH+ 636.4 D.6.2 ##STR00309## Chemical Name:
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino] butyl]-N'-phenyl urea Analytical
Data: MS: MH+ 586.3 D.6.3 ##STR00310## Chemical Name:
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino] butyl]-N'-heptyl urea Analytical
Data: MS: MH+ 608.4 D.6.4 ##STR00311## Chemical Name:
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino] butyl]-N'-(1-naphthyl) urea
Analytical Data: MS: MH+ 636.3; 1H-NMR (CDCl3): 8.08 (s, br, 1H);
7.98 (m, 1H); 7.79 (m, 2H); 7.57 (d, J = 8.2 Hz, 1H); 7.51-7.35 (m,
4H); 7.36 (d, J = 7.5 Hz, 1H); 7.17 (s, br, 1H); 6.67 (d, br, J =
6.6 Hz, 1H); 4.49 (m, 1H); 4.20 (dd, J = 8.5, 1.9 Hz, 1H); 3.39 (m,
1H); 3.20 (m, 1H); 3.04 (m, 1H); 2.26 (m, 1H); 2.08 (m, 2H); 1.93
(t, J = 5.6 Hz, 1H); 1.89-1.55 (m, 7H); 1.39 (m, 1H); 1.32 (s, 3H);
1.31 (m, 1H); 1.21 (s, 3H); 1.20 (m, 1H); 0.85 (d, J = 6.0 Hz, 6H);
0.79 (s, 3H). D.6.5 ##STR00312## Chemical Name
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]butyl]- N'-undecylurea Analytical
Data: MS: MH+ 664.4 D.6.6 ##STR00313## Chemical Name:
N-[(1S,2R)-1-[[[(1R)-1-[(3 aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-2-
hydroxypropyl]-N'-undecylurea Analytical Data: MS: [MH]+ 564.40
D.6.7 ##STR00314## Chemical Name:
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino]
butyl]-N'-[5-(ethoxycarbonyl)pentyl] urea Analytical Data: MS:
[MH]+ 652.40 D.6.8 ##STR00315## Chemical Name:
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl] amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino] butyl]-N'-(4-butylphenyl) urea
Analytical Data: MS: [M]H+ 642.5 D.6.9 ##STR00316## Chemical Name:
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino] butyl]-N'-(4-heptyloxylphenyl)
urea Analytical Data: MS: [M]H+ 700.7
Example D.7
Boronic acid,
[(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[[(E)-3-(naphthalen-2-
-yl)prop-2-enoyl]amino]-1-oxopentyl]amino]-3-methylbutyl]-
##STR00317##
[0531] To a suspension of PS-HOBT
(1-hydroxybenzotriazole-6-sulfonamidomethyl polystyrene, 277 mg,
0.31 mmol, loading 1.12 mmol/g) in DCM (6 mL) and DMF (0.6 mL),
3-naphthalen-2-yl-acrylic acid (91.2 mg, 0.46 mmol), DIC
(Diisopropylcarbodiimide, 0.22 mL, 1.40 mmol) and DIPEA (0.05 mL,
0.19 mmol) were added. The suspension was shaken for 3 hours at
room temperature and then the resin was filtered under nitrogen and
washed several times with DMF (3.times.5 mL), DCM (3.times.5 mL),
DMF (3.times.5 mL) and THF (3.times.5 mL). The well dried resin was
suspended in DCM (6 mL) and DMF (0.6 mL) and
[(1R)-1-[[(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]ami-
no]-3-methylbutyl]-boronic acid hydrochloride salt of Example C.2
(50 mg, 0.14 mmol) and DIPEA (0.06 mL, 0.20 mmol) were added. The
reaction mixture was shaken overnight at room temperature. The
resin was filtered off and washed with DMF (10 mL) and DCM (2 mL)
and the solvent was concentrated to dryness. Purification of the
crude compound by ISOLUTE SPE-SI normal phase cartridge (DCM 1,
MeOH 1), afforded the title compound (25 mg, yield 35%).
[0532] NMR (DMSO+D.sub.2O, 343 K): 8.06 (s, 1H); 7.95 (d, J=9.0 Hz,
1H); 7.94 (m, 2H); 7.72 (d, 1H); 7.61 (d, J=14.9 Hz, 1H); 7.55 (d,
J=9.0 Hz, 1H); 7.55 (m, 2H); 6.89 (d, J=14.9 Hz, 1H); 4.40 (m, 1H);
3.30-3.10 (m, 3H); 1.82 (m, 1H); 1.73-1.53 (m, 4H); 1.50-1.32 (m,
2H); 0.87 (d, J=6.1 Hz, 3H); 0.86 (d, J=6.1 Hz, 3H).
[0533] LC-MS 495.0, [M-18]H+. ESI POS; AQA; spray 5 kV/skimmer: 15
V/probe 250 C.
[0534] Further compounds prepared fundamentally in accordance with
the above experimental procedures are reported in Table D-7.
TABLE-US-00013 TABLE D-7 Ex # Structure Chemical Name and
Analytical Data D.7.1 ##STR00318## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl] amino]-2-[[(2E)-3-(2-
methoxyphenyl)-1-oxoprop- 2-enyl]amino]-1-
oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: MH+ 475.0
D.7.2 ##STR00319## Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl] amino]-2-[((E)-2-
methyl-3-phenylacryl)amino]- 1-oxopentyl]amino]- 3-methylbutyl]
Analytical Data: MS: [M-18]H+ 458.0 D.7.3 ##STR00320## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]
amino]-2-[(4-(4- methylphenyl)butanoyl)amino]-1-
oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M-18]H+ 474.0
D.7.4 ##STR00321## Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl] amino]-2[((2RS)-2-
phenylpropanoyl)amino]- 1-oxopentyl]amino]-3- methylbutyl]
Analytical Data: MS: [M-18]H+ 447.2 D.7.5 ##STR00322## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]
amino]-2-[(2-(4- isopropylphenoxy)acetyl)amino]-1-
oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M-18]H+ 491.5
D.7.6 ##STR00323## Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl] amino]-2-[(5-oxo-5-
phenylpentanoyl)amino]- 1-oxopentyl]amino]-3- methylbutyl]
Analytical Data: MS: [M-18]H+ 489.5 D.7.7 ##STR00324## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]
amino]-2-[[(4RS)-1- [(1,1-dimethylethoxy)carbonyl]
piperidine-4-carbonyl]amino]- 1-oxopentyl]amino]-3- methylbutyl]
Analytical Data: MS: [M-18]H+ 526.1 D.7.8 ##STR00325## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]
amino]-2-[(4- diethylaminobenzoyl)amino]- 1-oxopentyl]amino]-
3-methylbutyl] Analytical Data: MS: [M-18]H+ 508.1 D.7.9
##STR00326## Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl] amino]-2-[((E)-2-
methylhex-2-enoyl)amino]- 1-oxopentyl]amino]-3- methylbutyl]
Analytical Data: MS: [M-18]H+ 443.0 D.7.10 ##STR00327## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]
amino]-2-[(tiophen-3- carbonyl)amino]-1-oxopentyl]
amino]-3-methylbutyl] Analytical Data: MS: [M-18]H+ 425.6 D.7.11
##STR00328## Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl] amino]-2-[(4-isopropylbenzoyl)
amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical Data: MS:
[M-18]H+ 461.3 D.7.12 ##STR00329## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]
amino]-2-[(5-methylthiophene- 2-carbonyl)amino]-1-
oxopentyl]amino]-3- methylbutyl] Analytical Data: MS: [M-18]H+
439.3 D.7.13 ##STR00330## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]
amino]-2-[(benzoyl)amino]-1- oxopentyl]amino]-3- methylbutyl]
Analytical Data: MS: [M-18]H+ 419.4 D.7.14 ##STR00331## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]- 2-[((E)-2-butenoyl)amino]-1-
oxopentyl]amino]-3- methylbutyl] Analytical Data: MS: [M-18]H+
383.2 D.7.15 ##STR00332## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-
2-[((E)-penta-2,4-dienoyl)amino]- 1-oxopentyl]amino]-3-
methylbutyl] Analytical Data: MS: [M-18]H+ 395.4 D.7.16
##STR00333## Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]- 2-[(3,3-dimethyl-butanoyl)amino]-
1-oxopentyl]amino]-3- methylbutyl] Analytical Data: MS: [M-18]H+
413.0 D.7.17 ##STR00334## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]
amino]-2-[[5-(2,5-dimethylphenoxy)- 2,2-dimethylpentanoyl]amino]-
1-oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M-18]H+
547.2 D.7.18 ##STR00335## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]
amino]-2-[(2,2-dimethylpentanoyl) amino]-1-oxopentyl]amino]-3-
methylbutyl] Analytical Data: MS: [M-18]H+ 427.5 D.7.19
##STR00336## Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl] amino]-2-[[4-(thiophen-2-
yl)butanoyl]amino]-1- oxopentyl]amino]-3- methylbutyl] Analytical
Data: MS: [M-18]H+ 467.5 D.7.20 ##STR00337## Chemical Name: Boronic
acid, [(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-
2-[[5-(4-fluorophenyl)pentanoyl] amino]-1-oxopentyl]amino]-3-
methylbutyl] Analytical Data: MS: [M-18]H+ 493.4 D.7.21
##STR00338## Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]- 2-[(2,2-dimethylhexanoyl)amino]-
1-oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M-18]H+
441.0 D.7.22 ##STR00339## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-
2-[(hex-2,4-enoyl)amino]-1- oxopentyl]amino]-3-methylbutyl]
Analytical Data: MS: [M-18]H+ 409.3 D.7.23 ##STR00340## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]- 2-[[3-(thiophen-2-yl)propenoyl]
amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical Data: MS:
[M-18]H+ 451.4 D.7.24 ##STR00341## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-
2-[(5-cyclohexylpentanoyl)amino]- 1-oxopentyl]amino]-
3-methylbutyl] Analytical Data: MS: [M-18]H+ 481.1 D.7.25
##STR00342## Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]- 2-[((3R)-3,7-dimethyloct-6-
enoyl)amino]-1-oxopentyl]amino]- 3-methylbutyl] Analytical Data:
MS: [M-18]H+ 467.3 D.7.26 ##STR00343## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-
2-[[3-[(4-methylbenzyl)sulfanyl] propanoyl]amino]-1-oxopentyl]
amino]-3-methylbutyl] Analytical Data: MS: [M-18]H+ 507.0 D.7.27
##STR00344## Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-
2-[(4-pyrrol-1-ylbenzoyl)amino]-1- oxopentyl]amino]-3-methylbutyl]
Analytical Data: MS: [M-18]H+ 484.4 D.7.28 ##STR00345## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-
2-[(5-fluoro-2-methoxybenzoyl)amino]-
1-oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M-18]H+
466.9 D.7.29 ##STR00346## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-
2-[((2S)-2-methylbutanoyl)amino]- 1-oxopentyl]amino]-3-methylbutyl]
Analytical Data: MS: [M-18]H+ 399.0 D.7.30 ##STR00347## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-
[(cyclopropanecarbonyl)amino]-1- oxopentyl]amino]-3-methylbutyl]
Analytical Data: MS: [M-18]H+ 383.0 D.7.31 ##STR00348## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]- 2-[(4-ethoxybenzoyl)amino]-1-
oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M-18]H+ 463.5
D.7.32 ##STR00349## Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]- 2-[((E)-3-(4-bromophenyl)prop-2-
enoyl)amino]-1-oxopentyl]amino]- 3-methylbutyl] Analytical Data:
MS: [M-18]H+ 523.6 D.7.33 ##STR00350## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-
2-[[(2S)-2-(6-methoxynaphthalen- 2-yl)-propanoyl]amino]-1-
oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M-18]H+ 527.5
D.7.34 ##STR00351## Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]- 2-[[1-(4-methoxyphenyl)-
cyclopropanecarbonyl]amino]-1- oxopentyl]amino]-3-methylbutyl]
Analytical Data: MS: [M-18]H+ 489.4 D.7.35 ##STR00352## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]- 2-[(3-fluoro-4-methoxybenzoyl)
amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical Data: MS:
[M-18]H+ 466.9 D.7.36 ##STR00353## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-
2-[[(E)-3-(naphthalen-2-yl)prop-2- enoyl]amino]-1-oxopentyl]amino]-
3-methylbutyl] Analytical Data: MS: [M-18]H+ 495.0; 1H-NMR: (DMSO +
D2O, 343 K): 8.06 (s, 1H); 7.95 (d, J = 9.0 Hz, 1H); 7.94 (m, 2H);
7.72 (d, 1H); 7.61 (d, J = 14.9 Hz, 1H); 7.55 (d, J = 9.0 Hz, 1H);
7.55 (m, 2H); 6.89 (d, J = 14.9 Hz, 1H); 4.40 (m, 1H); 3.30-3.10
(m, 3H); 1.82 (m, 1H); 1.73-1.53 (m, 4H); 1.50-1.32 (m, 2H); 0.87
(d, J = 6.1 Hz, 3H); 0.86 (d, J = 6.1 Hz, 3H). D.7.37 ##STR00354##
Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-
2-[(4-fluoro-3-methylbenzyl)amino]-
1-oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M-18]H+
451.3 D.7.38 ##STR00355## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-
2-[[[[[(9H-fluoren-9-yl)methoxy] carbonyl]amino]butanoyl]
amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical Data: MS:
[M-18]H+ 622.2 D.7.39 ##STR00356## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-
2-[(4-bromobenzoyl)amino]-1- oxopentyl]amino]-3-methylbutyl]
Analytical Data: MS: [M-18]H+ 497.1 D.7.40 ##STR00357## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-
2-[(3-butenoyl)amino]-1-oxopentyl] amino]-3-methylbutyl] Analytical
Data: MS: [M-18]H+ 383.2 D.7.41 ##STR00358## Chemical Name: Boronic
acid, [(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-
2-[(undecanoyl)amino]-1-oxopentyl] amino]-3-methylbutyl] Analytical
Data: MS: [M-18]H+ 483.4 D.7.42 ##STR00359## Chemical Name: Boronic
acid, [(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-
2-[[4-(acetylamino)butanoyl]amino]- 1-oxopentyl]amino]-
3-methylbutyl] Analytical Data: MS: [M-18]H+ 442.2 D.7.43
##STR00360## Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]- 2-[(6-phenylhexanoyl)amino]-1-
oxopentyl]amino]-3- methylbutyl]- Analytical Data: MS: [M-18]H+
489.27 D.7.44 ##STR00361## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-
2-[(5-phenylpentanoyl)amino]-1- oxopentyl]amino]-3-methylbutyl]-
Analytical Data: MS: [M-18]H+ 475.23 D.7.45 ##STR00362## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]- 2-[(3-methoxypropanoyl)amino]-1-
oxopentyl]amino]-3-methylbutyl]- Analytical Data: MS: [M-18]H+
401.16 D.7.46 ##STR00363## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-
2-[[2,2-dimethyl-3-(2-methylpropenyl)-
cyclopropanecarbonyl]amino]-1- oxopentyl]amino]-3-methylbutyl]-
Analytical Data: MS: [M-18]H+ 465.29 D.7.47 ##STR00364## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]- 2-[(3-methoxycyclohexanecarbonyl)
amino]-1-oxopentyl]amino]-3- methylbutyl]- Analytical Data: MS:
[M-18]H+ 455.57 D.7.48 ##STR00365## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-
2-[[3-(1H-indol-3-yl)-propanoyl] amino]-1-oxopentyl]amino]-
3-methylbutyl]- Analytical Data: MS: [M-18]H+ 486.24 D.7.49
##STR00366## Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-
2[((RS)-2-cyclopent-2-enyl-acetyl) amino]-1-oxopentyl]amino]-3-
methylbutyl] Analytical Data: MS: [M-18]H+ 422.99 D.7.50
##STR00367## Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-
2[(5-thiophen-2-yl-pentanoyl)amino]-
1-oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M-18]H+
481.19 D.7.51 ##STR00368## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-2-
[(6-oxo-heptanoyl)amino]-1-oxopentyl] amino]-3-methylbutyl]
Analytical Data: MS: [M-18]H+ 441.24 D.7.52 ##STR00369## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-
[(7-oxo-octanoyl)amino]-1-oxopentyl] amino]-3-methylbutyl]
Analytical Data: MS: [M-18]H+ 455.47 D.7.53 ##STR00370## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2- [(hexanoyl)amino]-1-oxopentyl]
amino]-3-methylbutyl] Analytical Data: MS: [M-18]H+ 413.06 D.7.54
##STR00371## Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2- [(heptanoyl)amino]-1-oxopentyl]
amino]-3-methylbutyl] Analytical Data: MS: [M-18]H+ 427.14 D.7.55
##STR00372## Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-
[(3-octyloxy-propanoyl)amino]-1-
oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M-18]H+
499.17 D.7.56 ##STR00373## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-2-
[(benzothiazol-6-carbonyl)amino-1- oxopentyl]amino]-3-methylbutyl]
Analytical Data: MS: [M-18]H+ 476.31 D.7.57 ##STR00374## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-
[(undec-2-enoyl)amino]-1-oxopentyl] amino]-3-methylbutyl]
Analytical Data: MS: [M-18]H+ 481.41 D.7.58 ##STR00375## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]- 2-[(9-decenoyl)amino]-1-
oxopentyl]amino]-3- methylbutyl] Analytical Data: MS: [M-18]H+
467.31 D.7.59 ##STR00376## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-2-
[(tetradecanoyl)amino]-1- oxopentyl]amino]-3-methylbutyl]
Analytical Data: MS: [M-18]H+ 525.10
[0535] Further compounds prepared according to the above procedure
for Example D.7 are reported in Table D-7A.
TABLE-US-00014 TABLE D-7A Chemical Name and Ex # Structure
Analytical Data D.7.60 ##STR00377## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]
amino]-2-[(11-cianoundecanoyl) amino]-1-oxopentyl]amino]-3-
methylbutyl] Analytical Data: MS: [M-18]H+ 508.5 D.7.61
##STR00378## Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl] amino]-2-[(9-cyanononanoyl)
amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical Data: MS:
[M-18]H+ 480.1
Example D.8
Decanamide,
N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-me-
thano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxyp-
ropyl]-
##STR00379##
[0537] Decanoic acid (220 mg, 1.28 mmol, 1.2 eq.) was dissolved in
DMF dry (15 ml) at r.t., TBTU (410 mg, 1.28 mmol, 1.2 eq.) was
added and the resulting solution was stirred for 10'. The mixture
was cooled at 0.degree.-5.degree. C., NMM (0.35 ml, 3.2 mmol, 3
eq.) was added and then (2S)-amino-(3R)-hydroxy-butyric amide,
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-metha-
no-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]hydrochloride
salt, of Example C.3, (430 mg, 1.067 mmol, 1 eq.) was added. The
solution was stirred for 2 h, then was poured in water (200 ml) and
extracted with ethyl acetate (100 ml). The organic layer was washed
with the following solutions: citric acid 2% (20 ml), sodium
bicarbonate 2% (20 ml), NaCl 2% (25 ml). The organic solution was
dried over sodium sulphate anhydrous, filtered and evaporated under
reduced pressure to give 600 mg of oil that was purified by silica
gel chromatography (ethyl acetate/n-hexane 1/1) to give 540 mg of
white solid that was suspended overnight in diethyl ether (5 ml)
and n-hexane (20 ml). The suspension was filtered to give 110 mg of
white solid. Yield 20%.
[0538] Analytical data: m.p. 108.degree.-110.degree. C., TLC silica
gel (n-hexane/ethyl acetate 1/1 r.f. 0.33). E.A. calculated C
(66.91%), H (10.26%), N (5.38%), B (2.08%). found C (66.82%), H
(10.61%), N (5.35%), B (1.93%).
[0539] .sup.1H-NMR (DMSO-d.sub.6) .delta..sub.H: 8.81 (1H, br);
7.68 (1H, d, J=8.80 Hz); 4.93 (1H, d, J=5.2); 4.28 (1H, dd, J=8.8,
4.3); 4.05 (1H, dd, J=8.6, 1.8); 3.92 (1H, m); 2.52 (1H, m); 2.20
(1H, m), 2.17 (2H, t, J=7.1); 2.00 (1H, m); 1.83 (1H, t, J=5.8);
1.78 (1H, m); 1.64 (1H, m); 1.62 (1H, m); 1.49 (2H, m); 1.34 (1H,
d, J=10.0); 1.31-1.17 (21H, m); 1.04 (3H, d, J=6.4); 0.91-0.83 (9H,
m); 0.81 (3H, s).
[0540] Further compounds prepared according to the above procedure
include the following:
Example D.8.1
(2S)-2-[(Benzyloxycarbonyl)amino]-4-methylpentanamide,
N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-me-
thano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxyp-
ropyl]-
##STR00380##
[0542] Analytical data: TLC (CHCl.sub.3 9/MeOH 1, R.f. 0.63), m.p.
38.degree.-40.degree. C., E.A. calculated C (64.60%), H (8.54%), N
(6.85%). found C (62.44%), H (8.24%), N (7.47%).
[0543] .sup.1H NMR (DMSO-d.sub.6) .delta..sub.H: 8.78 (1H, br);
7.82 (1H, d, J=8.60 Hz); 7.52 (1H, d, J=8.1); 7.40-7.27 (6H, m);
5.02 (2H, br s); 5.00 (1H, d, J=5.1); 4.28 (1H, dd, J=8.6, J=4.2);
4.12 (1H, q, J 7.8); 4.05 (1H, dd, J=8.6, J=1.8); 3.94 (1H, m);
2.52 (1H, m); 2.19 (1H, m); 2.01 (1H, m); 1.83 (1H, t, J=5.8); 1.78
(1H, m); 1.74-1.55 (5H, m); 1.46 (2H, m); 1.32 (1H, d, J=10.1);
1.24 (3H, s); 1.22 (3H, s); 1.04 (3H, d, J=6.2); 0.91-0.82 (12H,
m); 0.80 (3H, s).
Example D.8.2
10-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-decanoic-amide-N-[(1S),(2R)-2-hyd-
roxy,
1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1-
,3,2-benzodioxaborol-2-yl]-3-methylbutyl]aminocarbonyl]-propyl]-
##STR00381##
[0545] Analytical data: TLC (CHCl.sub.3 9/MeOH 1 R.f. 0.83), E.A.
calculated C (66.52%), H (8.43%), N (6.37%). found C (66.76%), H
(8.48%), N (6.31
[0546] .sup.1H NMR (DMSO-d.sub.6) .delta..sub.H: 8.80 (1H, br);
7.85 (4H, m), 7.67 (1H, d, J=8.80 Hz); 4.93 (1H, d, J=5.5), 4.28
(1H, dd, J=8.6, 4.0); 4.04 (1H, dd); 3.92 (1H, m); 3.56 (2H, t,
J=8.1); 2.49 (1H, m); 2.23-2.12 (3H, m); 2.00 (1H, m); 1.82 (1H, t,
J=6.6); 1.78 (1H, m); 1.73-1.53 (5H, m); 1.48 (2H, m); 1.33 (1H, d,
J=10.1); 1.31-1.17 (20H, m); 1.03 (3H, d, J=6.2); 0.84 (6H, d,
J=6.6); 0.80 (3H, s).
[0547] Further compounds prepared according to the above procedures
for Example D.8, D.8.1 and D.8.2 are reported in Table D-8.
TABLE-US-00015 TABLE D-8 Ex # Structure Chemical Name D.8.3
##STR00382## Chemical Name: 4-(Pyridin-3-yl)benzamide, N-
[(1S,2R)-1-[[[(1R)-1-[(3aS,4S, 6S,7aR)-hexahydro-3a,5,5-
trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]- 2-hydroxypropyl]. Analytical Data:
.sup.1H NMR (DMSO-d.sub.6): 9.02 (1 H, s); 8.99 (1 H, s); 8.63 (1
H, d, J = 4.7); 8.22 (1 H, d, J = 8.4); 8.17 (1 H, d, J = 8.1);
8.04 (2 H, d, J = 8.3); 7.89 (2 H, d, J = 8.3); 7.53 (1 H, dd, J =
7.8, 4.8); 5.18 (1 H, d, J = 5.1); 4.53 (1 H, dd, J = 8.3, 5.1);
4.11-4.01 (2 H, m); 2.60-2.53 (1 H, m); 2.25-2.15 (1 H, m);
2.05-1.97 (1 H, m); 1.86-1.75 (2 H, m); 1.73-1.58 (2 H, m);
1.37-1.24 (3 H, m); 1.25 (3 H, s); 1.22 (3 H, s); 1.13 (3 H, d, J =
6.2); 0.85 (6 H, d, J = 6.4); 0.81 (3 H, s). D.8.4 ##STR00383##
Chemical Name: 2-Pyrazinecarbossamide, N-
[(1S,2R)-1-[[[(1R)-1-[(3aS,4S, 6S,7aR)-hexahydro-3a,5,5-
trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
melthylbutyl]amino]carbonyl]- 2-hydroxypropyl]. D.8.5 ##STR00384##
Chemical Name: Tridecanamide, N-[(1S,2R)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)- hexahydro-3a,5,5-trimethyl-4,6-
methano-1,3,2-benzodioxaborol- 2-yl]-3-methylbutyl]amino]
carbonyl]-2-hydroxypropyl]. D.8.6 ##STR00385## Chemical Name:
4-Phenylbenzamide, N-[(1S,2R)- 1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6- methano-1,3,2-benzodioxaborol-
2-yl]-3-methylbutyl] amino]carbonyl]-2-hydroxypropyl]. Analytical
Data: .sup.1H-NMR (DMSO-d6): 9.04 (1 H, bs); 8.18 (1 H, d, J =
8.5); 8.00 (2 H, d, J = 8.5); 7.81 (2 H, d, J = 8.4); 7.77-7.73 (2
H, m); 7.51 (2 H, t, J = 7.5); 7.43 (1 H, t, J = 7.3); 5.07 (1 H,
d, J = 6.2); 4.55-4.50 (1 H, m); 4.10-4.01 (2 H, m); 2.60-2.54 (1
H, m); 2.25-2.16 (1 H, m); 2.06-1.98 (1 H, m); 1.84 (1 H, t, J =
5.6); 1.82-1.76 (1 H, m); 1.74-1.60 (2 H, m); 1.35 (1 H, d, J =
10); 1.30-1.26 (2 H, m); 1.25 (3 H, s); 1.22 (3 H, s); 1.13 (3 H,
d, J = 6.2); 0.87-0.83 (6 H, m); 0.81 (3 H, s). D.8.7 ##STR00386##
Chemical Name: 2,2-Dimethydecanamide, N-
[(1S,2R)-1-[[[(1R)-1-[(3aS,4S, 6S,7aR)-hexahydro-3a,5,5-
trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]- 2-hydroxypropyl]. Analytical Data:
.sup.1H-NMR (DMSO-d6): 8.93 (1 H, bs); 7.03 (1 H, d, J = 8.6); 5.06
(1 H, d, J = 5.9); 4.36-4.31 (1 H, m); 4.06-4.01 (2 H, m);
3.99-3.92 (1 H, m); 2.24-2.14 (1 H, m); 1.90-1.76 (2 H, m);
1.70-1.58 (2 H, m); 1.50-1.42 (2 H, m); 1.38-1.32 (1 H, m);
1.28-1.20 (15 H, m); 1.19-1.12 (6 H, m); 1.12-1.08 (6 H, m); 1.03
(3 H, d, J = 6.3); 0.87-0.83 (9 H, m); 0.81 (3 H, s). D.8.8
##STR00387## Chemical Name: (4-phenoxy)benzamide, N-[(1S,2R)-
1-(1R)-1-[(3aS,4S,6S,7aR)- hexahydro-3a,5,5-trimethyl-4,6-
methano-1,3,2-benzodioxaborol-2- yl]-3-methylbutyl]amino]carbonyl]-
2-hydroxypropyl]. Analytical Data: .sup.1H-NMR (DMSO-d6): 9.01 (1
H, bs); 8.07 (1 H, d, J = 8.5); 7.96- 7.92 (2 H, m); 7.47-7.42 (2
H, m); 7.22 (1 H, t, J = 7.4); 7.11-7.06 (4 H, m); 5.04 (1 H, d, J
= 6.2); 4.52-4.47 (1 H, m); 4.10-3.98 (2 H, m); 2.60-2.52 (1 H, m);
2.24-2.16 (1 H, m); 2.08-1.98 (1 H, m); 1.86-1.74 (2 H, m);
1.62-1.58 (2 H, m); 1.35 (1 H, t, J = 10.0); 1.30-1.24 (2 H, m);
1.23 (3 H, s); 1.22 (3 H, s); 1.10 (3 H, d, J = 6.3); 0.86-0.84 (6
H, m); 0.80 (3 H, s). D.8.9 ##STR00388## Chemical Name:
5-Butyl-2-pyridinecarboxamide, N-[(1S,2R)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro- 3a,5,5-trimethyl-4,6-
methano-1,3,2-benzodioxaborol-2- yl]-3-methylbutyl]amino]carbonyl]-
2-hydroxypropyl]. D.8.10 ##STR00389## Chemical Name:
4-propoxybenzamide, N-[(1S,2R)- 1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6- methano-1,3,2-benzodioxaborol-
2-yl]-3-methylbutyl]amino] carbonyl]-2-hydroxypropyl]. Analytical
Data: .sup.1H NMR (DMSO-d6): 9.02 (1 H, s); 7.95 (1 H, d, J = 8.6);
7.87 (2 H, d, J = 8.8); 7.02 (2 H, d, J = 8.8); 5.03 (1 H, d, J =
6.2); 4.49 (1 H, dd, J = 8.4, 4.9); 4.03-3.98 (4 H, m); 2.58-2.50
(1 H, m); 2.24-2.15 (1 H, m); 2.04-1.97 (1 H, m); 1.85- 1.59 (7 H,
m); 1.23 (3 H, s); 1.22 (3 H, s); 1.18 (2 H, t, J = 7.1); 1.10 (3
H, d, J = 6.3); 0.99 (3 H, t, J = 7.4); 0.85 (3 H, d, J = 6.4);
0.84 (3 H, d, J = 6.4); 0.81 (3 H, s). D.8.11 ##STR00390## Chemical
Name: 3-(3-Pyridyl)benzamide, N-[(1S, 2R)-1-[[[(1R)-1-[(3aS,4S,6S,
7aR)-hexahydro-3a,5,5-trimethyl- 4,6-methano-1,3,2-benzodioxaborol-
2-yl]-3-methylbutyl]amino] carbonyl]-2-hydroxypropyl]. Analytical
Data: .sup.1H-NMR (DMSO-d6): 9.05-8.95 (2 H, m); 8.63 (1 H, dd, J =
1.53 Hz, J = 4.76 Hz); 8.39 (1 H, J = 8.51 Hz); 8.25 (1 H, m);
8.19-8.14 (1 H, m); 7.96-7.90 (2 H, m); 7.64 (1 H, t, J = 7.74 Hz);
7.57-7.51 (1 H, m); 5.053 (1 H, d, J = 6.06 Hz); 4.54 (1 H, dd, J =
5.36 Hz, J = 8.43 Hz); 4.12-4.00 (2 H, m); 2.61-2.54 (1 H, m);
2.25-2.14 (1 H, m); 2.05-1.95 (2 H, m); 1.82 (1 H, t, J = 5.55 Hz);
1.80- 1.74 1 H, m); 1.73-1.56 (1 H, m); 1.34 (1 H, d, J = 10.04
Hz); 1.31-1.25 (2 H, m); 1.22 (6 H, d, J = 9.04 Hz); 1.14 (3 H, d,
J = 6.33 Hz); 0.87-0.83 (6 H, m); 0.79 (3 H, bs). D.8.12
##STR00391## Chemical Name: 6-Phenyl-2-pyridinecarboxamide,
N-[(1S,2R)-1-[[[(1R)-1-(3aS,4S, 6S,7aR)-hexahydro-3a,5,5-
trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]- 2-hydroxypropyl]. Analytical Data:
.sup.1H-NMR (DMSO-d6): 9.20-8.95 (1 H, m); 8.76 (1 H, d, J = 8.55
Hz); 8.26-8.16 (4 H, m); 8.12 (1 H, t, J = 7.77 Hz); 8.02 (1 H, d,
J = 7.56 Hz); 7.60-7.47 (4 H, m); 5.27 (1 H, d, J = 4.97 Hz); 4.50
(1 H, dd, J = 4.22 Hz, J = 8.50 Hz); 4.16-4.07 (2 H, m); 2.65-2.56
(1 H, m); 2.25-2.15 (1 H, m); 2.09-1.98 (1 H, m); 1.84 (1 H, t, J =
5.62 Hz); 1.79-1.73 (1 H, m); 1.73-1.66 (1 H, m); 1.66-1.59 (1 H,
m); 1.40-1.26 (4 H, m); 1.23 (7 H, d, J = 10.89 Hz); 1.15-1.10 (4
H, m); 0.85 (7 H, d, J = 6.56 Hz); 0.79 (1 H, bs). D.8.13
##STR00392## Chemical Name: 3-propoxybenzamide, N-[(1S,2R)-
1-[[[(1R)-1-[(3aS,4S,6S,7aR)- hexahydro-3a,5,5-trimethyl-4,6-
methano-1,3,2-benzodioxaborol-2- yl]-3-methylbutyl]amino]carbonyl]-
2-hydroxypropyl]. Analytical Data: .sup.1H-NMR (DMSO-d6): 9.05-9.0
(1 H, m); 8.11 (1 H, d, J = 8.49 Hz); 7.48-7.43 (2 H, m); 7.40 (1
H, t, J = 7.80 Hz); 7.15-7.10 (1 H, m); 5.04 (1 H, d, J = 6.26 Hz);
4.49 (1 H, dd, J = 5.15, J = 8.43 Hz); 4.10-4.05 (1 H, m);
4.05-4.01 (1 H, m); 3.99 (2 H, t, J = 6.50 Hz); 2.25-2.15 (1 H, m);
2.05-1.96 (1 H, m); 1.83 (1 H, t, J = 5.56 Hz); 1.81- 1.72 (3 H,
m); 1.72-1.57 (2 H, m); 1.34 (1 H, d, J = 10.06 Hz); 1.31- 1.25 (2
H, m); 1.24 (4 H, bs); 1.22 (3 H, bs); 1.10 (3 H, d, J = 6.31 Hz);
1.02 (3 H, t, J = 7.40 Hz); 0.84 (6 H, dd, J = 1.84 Hz, J = 6.56
Hz), 0.81 (3 H, bs). D.8.14 ##STR00393## Chemical Name:
1-Bromonaphthalene-2-carboxamide,
N-[(1S,2R)-1-[[[(1R)-1-(3aS,4S,6S, 7aR)-hexahydro-3a,5,5-trimethyl-
4,6-methano-1,3,2-benzodioxaborol-
2-yl]-3-methylbutyl]amino]carbonyl]- 2-hydroxypropyl]. D.8.15
##STR00394## Chemical Name: 6-Bromonaphthalence-2-carboxamide,
N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,
7aR)-hexahydro-3a,5,5-trimethyl- 4,6-methano-1,3,2-benzodioxaborol-
2-yl]-3-methylbutyl]amino]carbonyl]- 2-hydroxypropyl]. D.8.16
##STR00395## Chemical Name: 3-Phenylbenzamide, N-[(1S,2R)-
1-[[[(1R)-1-[(3aS,4S,6S,7aR)- hexahydro-3a,5,5-trimethyl-4,6-
methano-1,3,2-benzodioxaborol- 2-yl]-3-methylbutyl]amino]
carbonyl]-2-hydroxypropyl]. Analytical Data: .sup.1H-NMR (DMSO-d6):
9.03 (1 H, s); 8.34 (1 H, d, J = 8.5); 8.18 (1 H, s); 7.87 (2 H, t,
J = 7.1); 7.75 (2 H, d, J = 7.8); 7.60 (1 H, t, J = 7.7); 7.52 (2
H, t, J = 7.6); 7.42 (1 H, t, J = 7.4); 5.05 (1 H, d, J = 6.2);
4.54 (1 H, dd, J = 8.4, 5.3); 4.10-4.00 (2 H, m); 2.60-2.53 (1 H,
m); 2.24-2.14 (1H, m); 2.05-1.97 (1 H, m); 1.82 (1 H, t, J = 5.5);
1.80-1.74 (1 H, m); 1.73- 1.57 (2 H, m); 1.37-1.22 (3 H, m); 1.24
(3 H, s); 1.21 (3 H, s); 1.13 (3 H, d, J = 6.2); 0.85 (3 H, d, J =
6.5); 0.84 (3 H, d, J = 6.5); 0.80 (3 H, s). D.8.17 ##STR00396##
Chemical Name: 4-(2-Fluorophenyl)benzamide,
N-[(1S,2R)-1-[[[(1R)-1-(3aS,4S, 6S,7aR)-hexahydro-3a,5,5-trimethyl-
4,6-methano-1,3,2-benzodioxaborol- 2-yl]-3-methylbutyl]amino]
carbonyl]-2-hydroxypropyl].
[0548] The intermediate carboxylic acids for the synthesis of
examples D.8.3, D.8.7, D.8.11, D.8.12 and D.8.13 were prepared
according to literature procedures. Compound 2,2-dimethyldecanoic
acid was prepared as described by Roth et al. in J. Med. Chem.
1992, 35, 1609-1617. Compounds 4-(3-pyridyl)benzoic acid,
3-(3-Pyridyl)benzoic acid and 6-phenyl-2-pyridinecarboxilic acid
were prepared according the procedure described by Gong et al. in
Synlett, 2000, (6), 829-831. Compound 3-propoxybenzoic acid was
prepared according the procedure described by Jones in J. Chem.
Soc. 1943, 430-432.
Example D.8.18
2-Pyrazinecarboxamide,
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-metha-
no-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-carbamoylet-
hyl]
##STR00397##
[0550] This compound has been prepared essentially according to the
above procedures for Example D.8, D.8.1 and D.8.2 starting from
(2S)-2-amino-3-carbamoylpropanamide,
N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-b-
enzodioxaborol-2-yl]-3-methylbutyl]; hydrochloride salt of Example
C.3.
[0551] .sup.1H-NMR (DMSO-d6): 9.20 (1H, d, J=1.29 Hz); 9.02 (1H, d,
J=8.52 Hz); 8.91 (1H, d, J=2.45 Hz); 8.81-8.76 (2H, m); 7.42 (1H,
s); 6.95 (1H, s); 5.00-4.80 (1H, m); 4.30-4.08 (1H, m); 2.85-2.72
(1H, m); 2.62-2.56 (2H, m); 2.25-2.15 (1H, m); 2.06-1.98 (1H, m);
1.84 (1H, t, J=5.54 Hz); 1.81-1.76 (1H, m); 1.72-1.58 (2H, m);
1.32-1.26 (1H, m); 1.23 (8H, d, J=5.36 Hz); 0.85-0.79 (9H, m).
Example D.8.19
Decanamide,
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-metha-
no-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-carbamoylet-
hyl]
##STR00398##
[0553] This compound has been prepared essentially according to the
above procedures for Example D.8, D.8.1 and D.8.2 starting from
(2S)-2-amino-3-carbamoylpropanamide,
N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-b-
enzodioxaborol-2-yl]-3-methylbutyl]; hydrochloride salt of Example
C.3.
Example D.8.20
4-Butylbenzamide,
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-metha-
no-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-carbamoylet-
hyl]
##STR00399##
[0555] This compound has been prepared essentially according to the
above procedures for Example D.8, D.8.1 and D.8.2 starting from
(2S)-2-amino-3-carbamoylpropanamide,
N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-b-
enzodioxaborol-2-yl]-3-methylbutyl]; hydrochloride salt of Example
C.3.
Example D.9
Decanamide,
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-metha-
no-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-[(4-methylb-
enzoyl)amino]ethyl]-
##STR00400##
[0557] Decanoic acid (330 mg, 1.95 mmol, 1.2 eq.) was dissolved in
DMF dry, (20 ml) and TBTU (620 mg, 1.95 mmol, 1.2 eq.) was added at
r.t. under nitrogen. The solution was stirred for 10', cooled at
0.degree.-5.degree. C. and NMM (0.53 ml, 4.9 mmol, 3 eq.) and
(2S)-2-amino-3-[(4-methylbenzoyl)amino]propanamide,
N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-b-
enzodioxaborol-2-yl]-3-methylbutyl]-, hydrochloride salt (800 mg,
1.58 mmol, 1 eq.) of Example C.4, were added and the resulting
mixture was stirred at r.t. for 3 h. The solution was poured in
water (200 ml) extracted with ethyl acetate (100 ml), washed with
solutions of citric acid 2% (50 ml), sodium bicarbonate 2% (50 ml),
NaCl 2% (50 ml). The organic solution was dried over sodium
sulphate anhydrous, filtered, evaporated and suspended in diethyl
ether (20 ml) for 30'. The suspension was filtered and dried to
give 330 mg of white solid. Yield 33%.
[0558] M.P.: 134.degree. C.-136.degree. C., TLC, silica gel,
(eluent n-hexane/ethyl acetate, r.f. 0.5). E.A. calculated C
(69.33%), H (9.37%), N (6.74%), B (1.73%). found C (%), H (%), N
(23%), B (%).
[0559] .sup.1H NMR (DMSO-d.sub.6) 8.74 (1H, d, J=3.5 Hz); 8.25 (1H,
t, J=5.6); 7.95 (1H, d, J=7.9); 7.71 (2H, d, J=8.1); 7.25 (2H, t,
J=8.1); 4.59 (1H, m); 4.1 (1H, dd, J=1.8, 8.8); 3.49 (2H, m); 2.59
(1H, m); 2.35 (3H, s); 2.20 (1H, m); 2.09 (1H, t, J=7.3); 2.02 (1H,
m); 1.83 (1H, t, J=5.5); 1.78 (1H, m); 1.62 (2H, m); 1.44 (2H, m);
1.36-1.21 (17H, m); 1.25 (3H, s), 1.22 (3H, s); 0.85 (3H, t,
J=6.8); 0.80 (9H, m).
Example D.10
2-S-decanoylamino-3-(hexanoylamino)-propionamide,
N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methan-
o-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]
##STR00401##
[0561] Decanoic acid (170 mg, 0.98 mmol, 1.2 eq.) was dissolved in
DMF dry, (15 ml) and TBTU (310 mg, 0.98 mmol, 1.2 eq.) was added at
r.t. under nitrogen. The solution was stirred for 20', cooled at
0.degree.-5.degree. C. and NMM (0.271 ml, 2.46 mmol, 2.5 eq.) and
2-S-amino-3-(hexanoylamino)-propionamide,
N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methan-
o-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl],
hydrochloride salt, (400 mg, 0.82 mmol, 1 eq.) of Example C.5, were
added and the resulting mixture was stirred at r.t. for 3 h. The
solution was poured in water (150 ml) extracted with ethyl acetate
(100 ml), washed with solutions of citric acid 2% (50 ml), sodium
bicarbonate 2% (50 ml), NaCl 2% (50 ml). The organic solution was
dried over sodium sulphate anhydrous, filtered, evaporated and
suspended in ethyl acetate (20 ml) for 30'. The suspension was
filtered and dried to give 230 mg of white solid. Yield 47%.
[0562] Analytical data: m.p. 135.degree.-137.degree. C., TLC silica
gel (eluent hexane/ethyl acetate 2/1, R.f.=0.27). E.A. calculated C
(67.64%), H (10.35%), N (6.96%). found C (66.93%), H (10.29%), N
(7.14%).
[0563] .sup.1H NMR (DMSO-d.sub.6) .delta..sub.H: 8.67 (1H, d, J=2.9
Hz); 7.83 (1H, d, J=8.2); 7.67 (1H, t, J=5.5); 4.41 (1H, m); 4.10
(1H, dd, J=1.5, 8.6); 3.25 (2H, m); 2.56 (1H, m); 2.20 (1H, m);
2.13-1.95 (5H, m); 1.84 (1H, t, J=5.5); 1.78 (1H, m); 1.64 (2H, m);
1.46 (4H, m); 1.35-1.15 (27H, m); 0.84 (9H, m); 0.79 (3H, s).
Example D.11
2-S-decanoylamino-3-(4-fluorosulfonylamino)propionamide,
N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methan-
o-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]
##STR00402##
[0565] Decanoic acid (160 mg, 0.94 mmol, 1.2 eq.) was dissolved in
DMF dry, (20 ml) and TBTU (300 mg, 0.94 mmol, 1.2 eq.) was added at
r.t. under nitrogen. The solution was stirred for 20', cooled at
0.degree.-5.degree. C. and NMM (0.259 ml, 2.36 mmol, 2.5 eq.) and
2-S-amino-3-(4-fluorosulfonylamino)propionamide,
N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methan-
o-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl],
hydrochloride salt, (430 mg, 0.78 mmol, 1 eq.) of Example C.6, were
added and the resulting mixture was stirred at r.t. for 2 h. The
solution was poured in water (200 ml) extracted with ethyl acetate
(100 ml), washed with the following solutions: citric acid 2% (50
ml), sodium bicarbonate 2% (50 ml), NaCl 2% (50 ml). The organic
solution was dried over sodium sulphate anhydrous, filtered,
evaporated and purified by silica gel chromatography (eluent
n-hexane/ethyl acetate 2/1). The solvent was evaporated and
n-hexane was added to give 100 mg of solid. Yield 19%.
[0566] Analytical data: m.p. 83.degree.-85.degree. C., TLC silica
gel (eluent hexane/ethyl acetate 2/1, R.f.=0.53).
[0567] .sup.1H NMR (DMSO-d.sub.6) .delta..sub.H: 8.45 (1H, d, J=3.8
Hz); 7.83 (3H, m); 7.63 (1H, t, J=6.2); 7.42 (2H, t, J=8.8); 4.40
(1H, m); 4.12 (1H, dd, J=1.5, 8.6); 2.95 (2H, m); 2.64 (1H, m);
2.21 (1H, m); 2.17 (2H, t, J=7.3); 2.01 (1H, m); 1.83 (1H, t,
J=5.5); 1.78 (1H, m); 1.62 (2H, m); 1.45 (2H, m); 1.4-1.1 (23H, m);
0.87-0.8 (9H, m); 0.79 (3H, s).
Example D.12
2-S-decanoylamino-3-(3,4-dimethoxyphenylacetamido)propionamide,
N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methan-
o-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]
##STR00403##
[0569] Decanoic acid (80 mg, 0.48 mmol, 1.2 eq.) was dissolved in
DMF dry, (20 ml) and TBTU (150 mg, 0.48 mmol, 1.2 eq.) was added at
r.t. under nitrogen. The solution was stirred for 20', cooled at
0.degree.-5.degree. C. and NMM (0.13 ml, 1.2 mmol, 2.5 eq.) and
2-S-amino-3-(3,4-dimethoxyphenylacetamido)propionamide,
N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methan-
o-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl],
hydrochloride salt, (230 mg, 0.4 mmol, 1 eq.) of Example C.7, were
added and the resulting mixture was stirred at r.t. for 2 h. The
solution was poured in water (200 ml) extracted with ethyl acetate
(100 ml), washed with the following solutions: citric acid 2% (50
ml), sodium bicarbonate 2% (50 ml), NaCl 2% (50 ml). The organic
solution was dried over sodium sulphate anhydrous, filtered,
evaporated and purified by silica gel chromatography (eluent
n-hexane/ethyl acetate 1/1). The solvent was evaporated to give 100
mg of glassy solid. Yield 35.7%. Analytical data: TLC silica gel
(eluent hexane/ethyl acetate 1/1, R.f.=0.53). E.A. calculated C
(67.13%), H (9.25%), N (6.02%). found C (65.38%), H (9.20%), N
(5.49).
[0570] .sup.1H NMR (DMSO-d.sub.6) .delta..sub.H: 8.65 (1H, d, J=3.5
Hz); 7.84 (2H, m); 6.83 (2H, m); 6.72 (1H, dd, J=1.7, 8.1); 4.43
(1H, m); 4.10 (1H, dd, J=1.8, 8.6); 3.72 (3H, s); 3.70 (3H, s);
3.30 (2H, s); 3.27 (2H, m); 2.58 (1H, m); 2.19 (1H, m); 2.02 (3H,
m); 1.84 (1H, t, J=5.5); 1.78 (1H, m); 1.63 (2H, m); 1.43 (2H, m);
1.35-1.15 (23H, m); 0.87-0.8 (9H, m); 0.79 (3H, s).
Example D.13
2-S-decanoylamino-3-(phenylureido)propionamide,
N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methan-
o-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]
##STR00404##
[0572] Decanoic acid (170 mg, 0.99 mmol, 1.2 eq.) was dissolved in
DMF dry, (20 ml) and TBTU (310 mg, 0.99 mmol, 1.2 eq.) was added at
r.t. under nitrogen. The solution was stirred for 20', cooled at
0.degree.-5.degree. C. and NMM (0.27 ml, 2.4 mmol, 2.5 eq.) and
2-S-amino-3-(phenylureido)propionamide,
N-[(1S)-1-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methan-
o-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl],
hydrochloride salt, (420 mg, 0.82 mmol, 1 eq.) of Example C.8, were
added and the resulting mixture was stirred at 0.degree. C. for 2
h. The solution was poured in water (200 ml) extracted with ethyl
acetate (100 ml), washed with the following solutions: citric acid
2% (50 ml), sodium bicarbonate 2% (50 ml), NaCl 2% (50 ml). The
organic solution was dried over sodium sulphate anhydrous,
filtered, evaporated and suspended in diethyl ether (20 ml) for 1
h, filtered and dried under vacuum to give 140 mg of white solid
that was purified by silica gel chromatography (n-hexane/ethyl
acetate 1/1). Yield 25%.
[0573] Analytical data: TLC silica gel (eluent hexane/ethyl acetate
1/1, R.f.=0.4).
[0574] .sup.1H NMR (DMSO-d.sub.6) .delta..sub.H: 8.73 (1H, d, J=3.1
Hz); 8.64 (1H, br s); 7.97 (1H, d, J=8.2); 7.36 (2H, d, J=8.1);
7.19 (2H, t, J=8.1); 6.87 (1H, t, J=8.1); 6.1 (1H, t, J=6.0); 4.44
(1H, m); 4.10 (1H, dd, J=1.8, 8.6); 3.41 (1H, m); 3.22 (1H, m);
2.59 (1H, m); 2.19 (1H, m); 2.10 (2H, t, J=7.3); 2.02 (1H, m); 1.84
(1H, t, J=5.5); 1.78 (1H, m); 1.64 (2H, m); 1.46 (2H, m); 1.35-1.15
(23H, m); 0.87-0.8 (9H, m); 0.79 (3H, s).
Example D.14
2-Aminoacetamide,
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-metha-
no-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4-[[imino(nit-
roamino)methyl]amino]butyl], Hydrochloride salt
##STR00405##
[0576] To a solution of N-Boc-Glycine (383 mg, 2.18 mmol), in
anhydrous dichloromethane (20 ml), N-methylmorpholine was added
(275 .mu.l, 2.5 mmol). The mixture was cooled to -15.degree. C.,
then isobutyl chloroformate (286 .mu.l, 1.2 mmol) was slowly added.
After 15 minutes
(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]pentanamide,
N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-b-
enzodioxaborol-2-yl]-3-methylbutyl]-hydrochloride salt of Example
C.1 (1.00 g, 2.0 mmol) and further N-methylmorpholine (275 .mu.l,
2.5 mmol) were added. The reaction mixture was stirred at
-15.degree. C.-10.degree. C. for 4 h, then concentrated to small
volume and partitioned between ethyl acetate (100 ml) and water (50
ml). The aqueous phase was further extracted with ethyl acetate (20
ml). The combined organic phases were dried over sodium sulfate and
concentrated. The residue was taken up with ethyl acetate (5 ml)
and the solution was dropwise added to hexane (120 ml) while
stirring at room temperature. The solid was collected by
decantation and dried under vacuum (1.18 g, 95%). Part of this
Boc-protected intermediate (1.08 g, 1.73 mmol) was dissolved in THF
(15 ml), then a 4N solution of HCl in dioxane was added. After
stirring for 5 hours at room temperature the mixture was
concentrated and the residue was triturated with diethyl ether (50
ml). The resulting white solid was collected by filtration, washed
with diethyl ether and dried under vacuum, yielding 856 mg of the
title compound (88% yield).
[0577] .sup.1H NMR (DMSO-d6): 8.76 (1H, d, J=3.1 Hz); 8.68 (1H, d,
J=8.1); 8.56 (1H, br); 8.06 (3H, m); 7.91 (2H, br); 4.43 (1H, m);
4.14 (1H, dd, J=8.6, J=1.6); 3.60 (2H, m); 3.15 (2H, br); 2.67 (1H,
m); 2.23 (1H, m); 2.04 (1H, m); 1.87 (1H, t, J=5.8); 1.81 (1H, m);
1.75-1.60 (3H, m); 1.52 (3H, m); 1.41-1.28 (3H, m); 1.27 (3H, s);
1.23 (3H, s); 0.86 (3H, d, J=6.4); 0.84 (3H, d, J=6.4); 0.81 (3H,
s).
Example D.15
3-Aminopropanamide,
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-metha-
no-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4-[[imino(nit-
roamino)methyl]amino]butyl]; hydrochloride salt
##STR00406##
[0579] To a solution of
3-[[(1,1-dimethylethoxy)carbonyl]amino]propanamide,
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-metha-
no-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4-[[imino(nit-
roamino)methyl-]amino]butyl]-, of Example D.3.118 (42 mg, 0.075
mmol) in diethyl ether (1.0 ml), cooled at 0.degree. C., a 10% v/v
solution of hydrogen chloride in diethyl ether (2 ml) was added.
The mixture was stirred for 5 hours while allowing to warm to room
temperature. The resulting solid was collected by filtration,
washed with diethyl ether (3.times.3 ml) and dried under vacuum,
giving 33 mg of the title compound (76% yield).
[0580] LC-MS 538.7, MH+. ESI POS; AQA; spray 4 kV/skimmer:
20V/probe 250 C.
[0581] Further compounds prepared according to the above Example,
starting from the corresponding Boc protected compound of Table
D.3, are reported in the following Table D-15.
TABLE-US-00016 TABLE D-15 Ex # Structure Chemical Name and
Analytical Data D.15.1 ##STR00407## Chemical Name:
(4RS)-piperidine-4-carboxamide, N-
[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)- hexahydro-3a,5,5-trimethyl-4,6-
methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-4- [[imino(nitroamino)methyl]amino]
butyl], HCl salt Analytical Data: MS: MH+ 578.1 D.15.2 ##STR00408##
Chemical Name: (RS)-Piperidine-2-carboxamide,
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6- methano-1,3,2-benzodioxaborol-2-
yl]-3-methylbulyl]amino]carbonyl]-
4-[[imino(nitroamino)methyl]amino] butyl]; HCl salt Analytical
Data: MS: [MH]+ 578.2 D.15.3 ##STR00409## Chemical Name:
(2S)-Piperidine-2-carboxamide, N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,
7aR)-hexahydro-3a,5,5-trimethyl- 4,6-methano-1,3,2-benzodioxaborol-
2-yl]-3-methylbutyl]amino]carbonyl]-
4-[[imino(nitroamino)methyl]amino] butyl]; HCl salt Analytical
Data: MS: [MH]+ 578.2 D.15.4 ##STR00410## Chemical Name:
(2R)-Piperidine-2-carboxamide, N-
[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-4-
[[imino(nitroamino)methyl]amino] butyl]; HCl salt Analytical Data:
MS: [MH]+ 578.8
Example D.16
Synthesis of Further Compounds
[0582] Following the procedures of Examples D.9-D.13, the following
compounds can be prepared by reaction of decanoic acid with the
intermediates of Example C.9.
TABLE-US-00017 D.16.1 Decanamide, N-[(1S)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-2-
(acetamido)ethyl]- ##STR00411## D.16.2 Decanamide,
N-[(1S)-1-[[[(1R)-1- [(3aS,4S,6S,7aR)-hexahydro-3a,5,5-
trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-2-(9-
fluorenylmethyloxycarbamoyl)ethyl]- ##STR00412## D.16.3 Decanamide,
N-[(1S)-1-[[[(1R)-1- [(3aS,4S,6S,7aR)-hexahydro-3a,5,5-
trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-2- (pentyl-ureido)ethyl]- ##STR00413##
D.16.4 Decanamide, N-[(1S)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- mcthylbutyl]amino]carbonyl]-2-
(methanesolfonamido)ethyl]- ##STR00414## D.16.5 Decanamide,
N-[(1S)-1-[[[(1R)-1- [(3aS,4S,6S,7aR)-hexahydro-3a,5,5-
trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-2- [(ethoxycarbonyl-succinyl]-
amide)ethyl]- ##STR00415## D.16.6 4-Butylbenzamide, N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)- hexahydro-3a,5,5-trimethyl-4,6-
methano-1,3,2-benzodioxaborol-2- yl]-3-methylbutyl]amino]carbonyl]-
2-[(benzyloxycarbonylamide)ethyl]- .sup.1H NMR (DMSO-d6): 9.79 (1
H, d); 8.32 (1 H, d); 7.8 (2 H, d); 7.3 (8 H, m); 5.05 (2 H, q) 4.7
(1 H, q); 4.1 (1 H, d); 3.45 (2 H, m); 2.6 (3 H, m); 2.2 (1 H, m);
2.0 (1 H, m); 1.85 (2 H, m); 1.65 (4 H, m); 1.3 (5 H, m); 1.25 (6
H, d) 0.9 (3 H, t); 0.80 (9 H, m). M.p. 95.degree.-100.degree. C.
##STR00416## D.16.7 4-butylbenzamide, N-[(1S)-1-
[[[(1R)-1-[(3aS,aS,6S,7aR)- hexahydro-3a,5,5-trimethyl-4,6-
methano-1,3,2-benzodioxaborol-2-
yl-]-3-methylbutyl]amino]carbonyl]- 2-(1H-pyrazol)ethyl]-
##STR00417## D.16.8 Decanamide, N-[(1S)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro- 3a,5,5-trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-2-
[(benzyloxycarbonylamide)ethyl]- .sup.1H NMR (DMSO-d6): 8.69 (1 H,
d); 7.85 (1 H, d); 7.35 (5 H, m); 7.05 (1 H, t); 5.05 (2 H, m) 4.45
(1 H, q); 4.1 (1 H, d); 3.3 (2 H, m); 2.65 (1 H, m); 2.2 (1 H, m);
2.1 (3 H, m); 1.85 (2 H, m); 1.65 (2 H, m); 1.45 (2 H, m); 1.25 (22
H, m); 0.8 (12 H, m) ##STR00418## D.16.9 4-Phenoxybenzamide,
N-[(1S)-1- [[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl-4,6- methano-1,3,2-benzodioxaborol-2-
yl]-3-methylbutyl]amino]carbonyl]-
2-[(benzyloxycarbonylamide)ethyl]- .sup.1H NMR (DMSO-d6): 9.8 (1 H,
d); 8.4 (1 H, d); 7.9 (2 H, d); 7.4 (2 H, t); 7.3 (6 H, m); 7.25 (2
H, m); 7.05 (4 H, m); 5.05 (2 H, q) 4.7 (1 H, q); 4.05 (1 H, d);
3.45 (2 H, m); 2.65 (1 H, m); 2.2 (1 H, m); 2.0 (1 H, m); 1.80 (2
H, m); 1.65 (2 H, m); 1.3 (4 H, m); 1.25 (6 H, d) 0.8 (9 H, m).
M.p. 100.degree.-103.degree. C. ##STR00419##
Example D.17
4-Butylbenzamide,
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-metha-
no-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-(aminoethyl-
)-hydrochloride salt
##STR00420##
[0584] 4-Butylbenzamide,
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3
a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]ami-
no]carbonyl]-2-[(benzyloxycarbonylamide)ethyl]-, of Example D.16.6,
(400 mg, 0.62 mmol, 1 eq.), was dissolved in 1,4-dioxane (10 ml)
and methanol (5 ml). To this solution, Pd/C 10% (40 mg) and HCl 4N
1,4-dioxane (1.1 eq.) were added. The mixture was hydrogenated at 1
bar. At the end of the reaction, Pd/C was filtered over celite, the
solvent removed under reduced pressure to give a white foam. Yield
95%, 320 mg. Analytical data:
[0585] .sup.1H NMR (DMSO-d6): 8.76 (1H, d); 8.55 (1H, d); 8.15 (3H,
br s); 7.95 (2H, d); 7.25 (2H, d); 4.8 (1H, m); 4.2 (1H, d); 2.80
(1H, m); 2.62 (2H, t); 2.23 (1H, m); 2.04 (1H, m); 1.87 (1H, t);
1.80 (1H, m); 1.75-1.50 (2H, m), (2H, m); 1.41-1.20 (6H, d), (6H,
m); 1.0-0.80 (3H, d); (3H, d); (3H, s), (3H t).
Example D.18
2-S-(4--Butylbenzoylamino)-3-(2-pyrazinocarbonylamino)-N-[(1S)-1-[[(1R)-1--
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxabo-
rol-2-yl]-3-methylbutyl]amino]carbonyl]
##STR00421##
[0587] 2-Pyrazine carboxylic acid, (76 mg, 0.61 mmol, 1.1 eq.) was
dissolved in DMF dry, (5 ml) and TBTU (200 mg, 0.61 mmol, 1.1 eq.)
was added at r.t. under nitrogen. The solution was stirred for 15',
cooled at 0.degree.-5.degree. C. and NMM (0.20 ml, 1.85 mmol, 3.3
eq.) and
4-butylbenzamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-tr-
imethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbon-
yl]-2-(aminoethyl)-hydrochloride salt, from Example D.17, (310 mg,
0.56 mmol, 1 eq.) were added and the resulting mixture was stirred
at 25.degree. C. for 4 h. The solution was poured in water (100 ml)
extracted with ethyl acetate (50 ml), washed with the following
solutions: citric acid 2% (50 ml), NaCl 2% (50 ml), sodium
bicarbonate 2% (50 ml), NaCl 2% (50 ml). The organic solution was
dried over sodium sulphate anhydrous, filtered, evaporated and
suspended in diethyl ether-n-hexane for 1 h, to give a white solid
that was filtered and dried under vacuum to give a white powder.
Yield 52%. 180 mg.
[0588] Analytical data: M.p. 70.degree.-72.degree. C.
[0589] .sup.1H NMR (DMSO-d6): 9.20 (1H, s); 9.0 (1H, t); 8.85 (1H,
d); 8.8 (1H, d); 8.78 (1H, d); 8.60 (1H, d); 7.82 (2H, d); 7.35
(2H, d); 4.8 (1H, m); 4.1 (1H, d); 3.80 (1H, m); 3.62 (1H, m); 2.82
(1H, b); 2.65 (2H, m); 2.2-2.0 (2H, m); 1.80 (1H, m); 1.75-1.50
(2H, m), (2H, m); 1.41-1.20 (6H, d), (6H, m); 1.0-0.80 (3H, d);
(3H, d); (3H, s), (3H t).
Example D.19
4-Butylbenzamide,
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-metha-
no-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-[4-fluoro-b-
enzenesulfonammide]ethyl]-
##STR00422##
[0591]
4-Butylbenzamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,-
5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]-
carbonyl]-2-[(benzyloxycarbonylamide)ethyl]-, of Example D.17,
(2.75 g, 5.02 mmol, 1 eq.), was dissolved in dry methylene chloride
at 0.degree.-5.degree. C. To this solution 4-fluorobenzenesulfonyl
chloride (1.07 g, 5.52 mmol, 1.1 eq.) was added and
N-methylmorpholine (NMM) (1.11 g, 11.04 mmol, 2.2 eq.) was added
dropwise, after few minutes. The mixture was stirred at 0-5.degree.
C. for 30', then at 10.degree. C. for 1 h. The solvent was removed
under reduced pressure, the crude was dissolved in Ethyl acetate
and washed with a solution of citric acid 2% (50 ml) then with a
solution of sodium bicarbonate 2% (50 ml) and a solution of sodium
chloride 2% (50 ml). The solution was dried over anhydrous sodium
sulfate and the solvent evaporated under reduced pressure. The
crude was purified by silica gel chromatography (eluent ethyl
acetate/n-hexane 1/2), the collected fractions have been evaporated
under reduced pressure and the white solid was suspended in diethyl
ether, filtered and dried under vacuum to give a white wax. Yield
60%, 2 g. Analytical data:
[0592] .sup.1H NMR (DMSO-d6): 8.60 (1H, d); 8.30 (1H, d); 7.85 (3H,
m); 7.8 (2H, d); 7.38 (2H, d); 7.30 (2H, d); 4.62 (1H, m); 4.15
(1H, d); 3.25 (2H, br); 2.61 (3H, m); 2.3-2.0 (1H, m); (1H, m);
1.80 (1H, m); 1.75-1.50 (2H, m), (2H, m); 1.41-1.20 (6H, d), (6H,
m); 1.0-0.80 (3H, d); (3H, d); (3H, s), (3H t).
Example D.20
4-Butylbenzamide,
N-[(1S)-1-[[[(1R)-1-[(3aS,aS,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-metha-
no-1,3,2-benzodioxaborol-2-yl-]-3-methylbutyl]amino]carbonyl]-2-[(2,5-dime-
thyl-2H-pyrazole) carbonylamino]ethyl]-
##STR00423##
[0594]
4-Butylbenzamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3
a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]ami-
no]carbonyl]-2-[(benzyloxycarbonylamide)ethyl]-, of Example D.17,
(0.9 g, 1.64 mmol, 1 eq.), was dissolved in dry dichloromethane (10
ml). The resulting solution was cooled to
0.degree.<T<5.degree. C. and N-methyl-morpholine (0.381 g,
3.78 mmol, 2.3 eq.) was added. To the mixture,
1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (Rn [55458-67-8])
(0.286 mg, 1.8 mmol, 1.1 eq.) was added. The mixture was stirred
for 1 h, then the temperature was raised to 20.degree. C. The
mixture was evaporated under reduced pressure, suspended in ethyl
acetate (50 ml), washed with 2% citric acid solution (30 ml), 2%
sodium bicarbonate (30 ml), 2% sodium chloride (30 ml). The organic
layer was dried over anhydrous sodium sulfate and evaporated under
reduced pressure. The crude was purified by silica gel
chromatography (eluent Ethyl acetate/n-hexane 8/2). The collected
fractions were evaporated to give a white powder, that was
suspended in diethyl ether and filtered to give the desired
compound. Yield 65%, 650 mg. Rf. 0.62.
[0595] Analytical data: M.p. 62.degree.-64.degree. C.
[0596] .sup.1H NMR (DMSO-d6): 8.82 (1H, d); 8.40 (2H, m); 7.85 (2H,
d); 7.3 (2H, d); 6.5 (1H, s); 4.8 (1H, m); 4.15 (1H, d); 3.9 (3H,
s); 3.61 (2H, m); 2.65 (3H, m); 2.25 (1H, m); 2.15 (3H, s); 2.0
(1H, m); 1.80 (1H, m); 1.75-1.50 (4H, m), 1.41-1.20 (5H, m), (6H,
m); 0.90 (3H, t); 0.8 (9H, m);
Example D.21
4-Butylbenzamide,
N-[(1S)-1-[[[(1R)-1-[(3aS,aS,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-metha-
no-1,3,2-benzodioxaborol-2-yl-]-3-methylbutyl]amino]carbonyl]-2-(4-methylp-
henyluriedosulfonylamino)ethyl]-
##STR00424##
[0598]
4-Butylbenzamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3
a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]ami-
no]carbonyl]-2-[(benzyloxycarbonylamide)ethyl]-, of Example D.17,
(0.7 g, 1.27 mmol, 1 eq.), was dissolved in dry THF (10 ml), the
solution was cooled at 0.degree.-5.degree. C. Triethylamine (0.4
ml, 1.8 mmol, 2.2 eq.) and (4-methylphenyl)-ureido-sulfonylchloride
(0.34 g, 1.38 mmol, 1.09 eq.) of example G.1.times. have been
added. The suspension was stirred at 25.degree. C. for 1 h, then
was poured in a citric acid 1% solution (30 ml) and extracted with
Ethyl acetate (50 ml). The organic solution was washed with sodium
chloride 2% solution, dried over anhydrous sodium sulfate, filtered
and evaporated under reduced pressure to give a crude that was
purified by silica gel chromatography (eluent Ethyl
acetate/n-hexane 1/1) Rf 0.64. The collected fractions have been
evaporated and the oil was coevaporated with diethyl ether to give
a white foam. Yield 31%, 280 mg.
[0599] Analytical data: M.p. 115.degree.-120.degree. C.
[0600] .sup.1H NMR (DMSO-d6): 8.80 (1H, s); 8.40 (1H, d); 7.82 (2H,
d); 7.3 (2H, d); 7.25 (2H, d); 7.00 (2H, d); 4.62 (1H, m); 4.15
(1H, d); 2.61 (3H, m); 2.3-2.0 (3H, s); 1.80 (1H, m); 1.75 (2H, m),
1.6 (4H, m), 1.2 (13H, m); 0.9 (3H, s), 0.8 (9H m).
Example D.22
4-Phenoxybenzamide,N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-t-
rimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbo-
nyl]-2-(3-phenyl-ureido)ethyl]-
##STR00425##
[0602] 4-Phenoxybenzamide,
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-metha-
no-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-(amino)ethy-
l]-hydrochloride salt, from example D.25.2, (1 g, 17 mmol, 1 eq.),
was dissolved in dry dichloromethane (30 ml) and
N-methyl-morpholine (0.2 g, 18.8 mmol, 1.1 eq.) was added. The
solution was cooled at 0.degree.-5.degree. C. and phenylisocyanate
(0.22 g, 17.7 mmol, 1.1 eq.) in dichloromethane (ml) was added. The
mixture was stirred for 1 h at 0.degree.-5.degree. C. The solution
was washed with sodium chloride 2% solution (50 ml), dried over
anhydrous sodium sulfate and evaporated under vacuum. The crude was
suspended in diethyl ether (20 ml), stirred for 2 h, filtered and
dried under vacuum at 50.degree. C. to give a white powder. Yield
74.3%, 0.84 g.
[0603] Analytical data: M.p. 143.degree.-145.degree. C.
[0604] .sup.1H NMR (DMSO-d6): 8.9 (1H, d); 8.75 (1H, s); 8.59 (1H,
d); 7.95 (2H, d); 7.45 (2H, t); 7.35 (2H, d); 7.2 (3H, m); 7.1 (4H,
m); 6.9 (1H, m); 6.25 (1H, t); 4.65 (1H, m); 4.10 (1H, d); 3.65
(1H, m); 3.4 (1H, m); 2.6 (1H, m); 2.2 (1H, m); 2.1 (1H, m); 1.85
(2H, m); 1.65 (2H, m), 1.3 (3H, m); (6H, d); 0.80 (9H, t).
Example D.23
4-Butylbenzamide,
N-[(1S)-1-[[[(1R)-1-[(3aS,aS,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-metha-
no-1,3,2-benzodioxaborol-2-yl-]-3-methylbutyl]amino]carbonyl]-2-(4-methylp-
henylsulfonylureido)ethyl]-
##STR00426##
[0606] 4-Butylbenzamide,
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3
a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]ami-
no]carbonyl]-2-(aminoethyl)-hydrochloride salt, from Example D.17,
(560 mg, 1.07 mmol, 1 eq.) was dissolved in dichloromethane dry (20
ml), and the solution was cooled at 0.degree.-5.degree. C.
N-methyl-morpholine (0.125 ml, 1.129 mmol, 1.1 eq,); and
4-toluenesulfonylisocyanate (0.22 g, 1.12 mmol, 1.1 eq,) were added
and the mixture was stirred at room temperature for 2 h. The
mixture was washed with a solution of citric acid 2% (20 ml) and a
sodium chloride 2% solution (25 ml). The organic layer was dried
over anhydrous sodium sulfate, filtered and evaporated under
reduced pressure. The crude was dissolved in diethyl ether (40 ml)
and the solvent was evaporated. The crude was suspended in n-hexane
(20 ml), stirred for 1 h at room temperature, filtered and dried
under vacuum at 50.degree. C. to give a white powder. Yield 75.6%,
0.55 g.
[0607] Analytical data: M.p. 168.degree.-170.degree. C.
[0608] .sup.1H NMR (DMSO-d6): 10.8 (1H, s); 8.75 (1H, d); 8.35 (1H,
d); 7.75 (4H, m); 7.35 (5H, m); 6.65 (1H, t); 4.5 (1H, t); 4.1 (1H,
d); 3.5 (1H, m); 3.25 (1H, m); 2.65 (3H, m); 2.3 (3H, d); 2.2 (1H,
m); 2.1 (1H, m); 1.80 (2H, m); 1.65 (4H, m), 1.3 (12H, m); 0.80
(12H, m).
Example D.24
Synthesis of Further Compounds
[0609] Following the procedures of Examples D.18-D.23, the
following compounds can be prepared by reaction of the
intermediates of Example D.17 or D.25 with the appropriate
commercially available carboxylic acids, acyl halides, sulphonyl
halides, isocyanates, sulphonylisocyanates, or with the compounds
of Examples G.14, G.15 and G.16. All the obtained compounds have
been characterized by .sup.1H-NMR.
TABLE-US-00018 TABLE D-24 D.24.1 ##STR00427## Chemical Name:
Decanamide, N-[(1S)-1-[[[(1R)-1- [(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-2- [4-fluoro-benzenesulfonammide]
ethyl]- D.24.2 ##STR00428## Chemical Name: Decanamide,
N-[(1S)-1-[[[(1R)-1- [(3aS,4S,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl]-3-
methylbulyl]amino]carbonyl]-2- [(4-sulfonamidophenyl)carbonyl-
amido]ethyl]- Analytical Data: .sup.1H NMR (DMSO-d6): 8.8 (1 H, d);
8.55 (1 H, t); 8.35 (1 H, d); 7.92 (2 H, d); 7.88 (2 H, d); 7.45 (2
H, s); 4.6 (1 H, t); 3.5 (2 H, m); 2.2 (1 H, m); 2.1 (2 H, m); 2.05
(1 H, m); 1.8 (2 H, m); 1.6 (2 H, m); 1.45 (3 H, m); 1.25 (24 H,
m); 1.65 (4 H, m), 0.80 (12 H, m). M.p. 178.degree.-181.degree. C.
D.24.3 ##STR00429## Chemical Name: 4-butylbenzamide, N-[(1S)-1-
[[[(1R)-1-[(3aS,aS,6S,7aR)- hexahydro-3a,5,5-
trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl-]-3-
methylbutyl]amino]carbonyl]-2- (acetamido)ethyl]- Analytical Data:
.sup.1H NMR (DMSO-d6): 8.8 (1 H, d); 8.5 (1 H, m), 8.0 (1 H, t),
7.8 (2 H, d); 7.25 (2 H, d); 7.2 (2 H, t); 4.7 (1 H, q); 4.1 (1 H,
d), 3.7-3.4 (2 H, m); 2.7 (2 H, t); 2.2 (1 H, m), 2.0 (1 H, m), 1.9
(1 H, t); 1.8 (3 H, s), 1.7-1.5 (4 H, m); 1.4-1.1 (10 H, m) 1.1 (1
H, t), 0.95 (3 H, t), 0.8 (9 H, m). M.p. 133.degree.-135.degree. C.
D.24.4 ##STR00430## Chemical Name: 4-butylbenzamide, N-[(1S)-1-
[[[(1R)-1-[(3aS,aS,6S,7aR)- hexahydro-3a,5,5-
trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl-]-3-
methylbulyl]amino]carbonyl]-2- (methanesulfonamido)ethyl]-
Analytical Data: .sup.1H NMR (DMSO-d6): 8.8 (1 H, d); 8.5 (1 H, m),
8.0 (1 H, t), 7.8 (2 H, d); 7.25 (2 H, d); 7.2 (2 H, t); 4.7 (1 H,
q); 4.1 (1 H, d), 3.7-3.4 (2 H, m); 2.9 (3 H, s), 2.7 (2 H, t); 2.2
(1 H, m), 2.0 (1 H, m), 1.9 (1 H, t); 1.7-1.5 (4 H, m); 1.4-1.1 (10
H, m) 1.1 (1 H, t), 0.95 (3 H, t), 0.8 (9 H, m). M.p.
53.degree.-55.degree. C. D.24.5 ##STR00431## Chemical Name:
4-butylbenzamide, N-[(1S)-1- [[[(1R)-1-[(3aS,aS,6S,7aR)-
hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl-]- 3-methylbutyl]amino]carbonyl]-2-
(propylureido)ethyl]- Analytical Data: .sup.1H NMR (DMSO-d6): 8.9
(1 H, s); 8.6 (1 H, d); 7.8 (2 H, d); 7.25 (2 H, d); 6.2 (1 H, t);
6.05 (1 H, t); 4.5 (1 H, t); 4.05 (1 H, t); 3.4 (1 H, m); 2.9 (1 H,
m); 2.65 (2 H, t); 2.2 (1 H, m); 2.0 (1 H, m); 1.8 (2 H, m); 1.65
(4 H, m); 1.2 (15 H, m), 0.80 (16 H, m). D.24.6 ##STR00432##
Chemical Name: 4-butylbenzamide, N-[(1S)-1-
[[[(1R)-1-[(3aS,aS,6S,7aR)- hexahydro-3a,5,5-
trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl-]-3-
methylbutyl]amino]carbonyl]-2-[(4-
methylphenyl)carbonylamino]ethyl]- Analytical Data: .sup.1H NMR
(DMSO-d6): 8.8 (1 H, d); 8.5 (2 H, m), 7.9 (2 H, d), 7.8 (2 H, d);
7.3 (2 H, d) 7.25 (2 H, d); 4.7 (1 H, q); 4.1 (1 H, d), 3.7-3.4 (2
H, m); 2.6 (3 H, m), 2.2 (1 H, m), 2.0 (1 H, m), 1.7-1.5 (4 H, m);
1.4-1.1 (12 H, m) 1.1 (1 H, t), 0.95 (3 H, t), 0.8 (12 H, m). M.p.
150.degree.-152.degree. C. D.24.7 ##STR00433## Chemical Name:
4-butylbenzamide, N-[(1S)-1- [[[(1R)-1-[(3aS,aS,6S,7aR)-
hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl-]- 3-methylbulyl]amino]carbonyl]-2-
[(1,1-dimethylethoxycarbonyl) amino]ethyl]- Analytical Data:
.sup.1H NMR (DMSO-d6): 8.8 (1 H, s); 8.25 (1 H, d); 7.8 (2 H, d);
7.3 (2 H, d); 6.9 (1 H, t); 4.65 (1 H, t); 4.1 (1 H, d); 2.65 (2 H,
m); 2.2 (1 H, m); 2.1 (1 H, m); 1.8 (2 H, m); 1.6 (4 H, m); 1.3 (20
H, m); 0.9-0.80 (12 H, m). D.24.8 ##STR00434## Chemical Name:
4-butylbenzamide, N-[(1S)-1- [[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbulyl]amino]carbonyl]-2-
[(thien-2-ylcarbonyl)amino]ethyl]- Analytical Data: .sup.1H NMR
(DMSO-d6): 8.8 (1 H, d); 8.5 (1 H, m), 8.0 (1 H, t), 7.80 (2 H, d);
7.7 (2 H, m); 7.3 (2 H, d); 7.2 (1 H, t); 4.7 (1 H, q); 4.1 (1 H,
d), 2.2 (1 H, m), 2.0 (1 H, m), 1.9 (1 H, t); 1.7-1.5 (4 H, m);
1.4-1.1 (10 H, m) 1.1 (1 H, t), 0.95 (3 H, t), 0.8 (9 H, m). D.24.9
##STR00435## Chemical Name: Decanamide, N-[(1S)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-2-
[(thien-2-ylcarbonyl)amino]ethyl]- Analytical Data: .sup.1H NMR
(DMSO-d6): 8.8 (1 H, d); 8.5 (1 H, m), 8.0 (1 H, t), 7.80 (2 H, d);
7.7 (2 H, m); 7.3 (2 H, d); 7.2 (1 H, t); 4.7 (1 H, q); 4.1 (1 H,
d), 3.5 (2 H, t), 2.9 (1 H, m); 2.8 (1 H, m); 2.4 (4 H, m); 2.2 (1
H, m), 2.0 (1 H, m), 1.9 (1 H, t); 1.7-1.5 (4 H, m); 1.4-1.1 (10 H,
m) 1.1 (1 H, t), 0.95 (3 H, t), 0.8 (9 H, m) .2.9 (1 H, m); 2.8 (1
H, m); 2.4 (4 H, m); 1.9 (1 H, m); 1.85 (1 H, m); 1.65 (2 H, m);
1.50 (2 H, m); 1.35 (1 H, m); 0.85 (12 H, m). M.p. 110.degree. C.
D.24.10 ##STR00436## Chemical Name: 4-butylbenzamide, N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)- hexahydro-3a,5,5-
trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-2- (hexanonylamino)ethyl]- Analytical
Data: .sup.1H NMR (DMSO-d6): 8.8 (1 H, d); 8.5 (1 H, d), 8.0 (1 H,
t), 7.80 (2 H, d); 7.3 (2 H, d); 4.7 (1 H, q); 4.1 (1 H, d), 3.5 (2
H, t), 2.6 (3 H, m), 2.2 (1 H, m), 2.0 (3 H, t), 1.9-1.75 (2 H, m);
1.7-1.5 (4 H, m); 1.5 (2 H, m), 1.4-1.1 (16 H, m), 0.95-0.8 (16 H,
m) D.24.11 ##STR00437## Chemical Name: 4-butylbenzamide, N-[(1S)-1-
[[[(1R)-1-[3aS,aS,6S,7aR)- hexahydro-3a,5,5-
trimethyl-4,6-methano,1,3,2- benzodioxaborol-2-yl-]-3-
methylbulyl]amino]carbonyl]-2- (cyclopropancarbonylamino)ethyl]-
Analytical Data: .sup.1H NMR (DMSO-d6): 8.8 (1 H, d); 8.5 (1 H, d),
8.0 (1 H, t), 7.80 (2 H, d); 7.3 (2 H, d); 4.7 (1 H, q); 4.1 (1 H,
d), 3.5 (2 H, t), 2.6 (3 H, m), ), 2.2 (1 H, m), 2.0 (1 H, m), 1.9
(1 H, t); 1.7-1.5 (4 H, m); 1.4-1.1 (10 H, m) 1.1 (1 H, t), 0.95 (3
H, t), 0.8 (9 H, m), 0.7 (4 H, m). D.24.12 ##STR00438## Chemical
Name: 4-Butylbenzamide, N-[(1S)-1- [[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5- trimethyl-4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-2-
(3-phenyl-ureido)ethyl]- Analytical Data: .sup.1H NMR (DMSO-d6):
8.9 (1 H, m); 8.8 (1 H, s), 8.5 (1 H, s), 7.9 (2 H, d), 7.5 (2 H,
d); 7.4 (2 H, d); 7.3 (2 H, d), 6.9 (1 H, t); 4.7 (1 H, q); 4.1 (1
H, d), 3.7-3.4 (2 H, m); 2.6 (3 H, m), 2.2 (1 H, m), 2.0 (1 H, m),
1.7-1.5 (4 H, m); 1.4-1.1 (12 H, m) 1.1 (1 H, t), 0.95 (3 H, t),
0.8 (9 H, m) D.24.13 ##STR00439## Chemical Name: 4-butylbenzamide,
N-[(1S)-1- [[[(1R)-1-[(3aS,4S,6S,7aR)- hexahydro-3a,5,5-
trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-2- [(N-methyl-2-pyrrolylcarbonylamide)
ethyl]- Analytical Data: .sup.1H NMR (DMSO-d6): 8.9 (1 H, d); 8.45
(1 H, d), 8.05 (1 H, t), 7.8 (2 H, d), 7.3 (2 H, d); 6.9 (1 H, s);
6.7 (1 H, t), 5.95 (1 H, t); 4.7 (1 H, q); 4.1 (1 H, d), 3.8 (3 H,
s); 3.6 (2 H, m); 2.6 (3 H, m), 2.2 (1 H, m), 2.05 (1 H, m), 1.8 (4
H, m); 1.3 (12 H, m) 0.91 (3 H, t), 0.8 (9 H, m). M.p.
88.degree.-92.degree. C. D.24.14 ##STR00440## Chemical Name:
4-butylbenzamide, N-[(1S)-1- [[[(1R)-1-[3aS,aS,6S,7aR)-
hexahydro-3a,5,5- trimethyl-4,6-methano,1,3,2-
benzodioxaborol-2-yl-]-3- methylbulyl]amino]carbonyl]-2-
[(3,4-dimethoxyphenyl) acetylamino]ethyl]- Analytical Data: .sup.1H
NMR (DMSO-d6): 8.8 (1 H, m); 8.4 (1 H, d), 8.1 (1 H, t), 7.9 (2 H,
d), 7.3 (2 H, d), 6.8 (1 H, s); 6.6 (2 H, t), 4.7 (1 H, q); 4.1 (1
H, d), 3.7-3.4 (2 H, m); 2.6 (3 H, m), 2.2 (1 H, m), 2.0 (1 H, m),
1.7-1.5 (4 H, m); 1.4-1.1 (12 H, m), 1.1 (1 H, t), 0.95 (3 H, t),
0.8 (9 H, m). D.24.15 ##STR00441## Chemical Name: 4-butylbenzamide,
N-[(1S)-1- [[[(1R)-1-[(3aS,4S,6S,7aR)- hexahydro-3a,5,5-
trimethyl-4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-2- (nicotinonylamino)ethyl]- Analytical
Data: .sup.1H NMR (DMSO-d6): 9.1 (1 H, s) 8.9 (1 H, m); 8.7 (1 H,
t), 8.6 (1 H, d), 8.5 (1 H, d), 8.1 (1 H, d), 7.9 (2 H, d), 7.5 (1
H, m), 7.3 (2 H, d), 4.7 (1 H, q); 4.1 (1 H, d), 3.7-3.4 (2 H, m);
2.6 (3 H, m), 2.2 (1 H, m), 2.0 (1 H, m), 1.7-1.5 (4 H, m); 1.4-1.1
(12 H, m) 1.1 (1 H, t), 0.95 (3 H, t), 0.8 (9 H, m). D.24.16
##STR00442## Chemical Name: 4-butylbenzamide, N-[(1S)-1-
[[[(1R)-1-[3aS,aS,6S,7aR)- hexahydro-3a,5,5-trimethyl-
4,6-methano,1,3,2- benzodioxaborol-2-yl-]-
3-methylbulyl]amino]carbonyl]- 2-[(4-sulfonylamino)
benzoylamino]ethyl]- Analytical Data: .sup.1H NMR (DMSO-d6): 8.9 (1
H, m); 8.7 (1 H, t), 8.6 (1 H, d), 8.0 (2 H, d), 7.9 (2 H, d), 7.8
(2 H, d) ,7.5 (2 H, s), 7.3 (2 H, d), 4.7 (1 H, q); 4.1 (1 H, d),
3.7-3.4 (2 H, m); 2.6 (3 H, m), 2.2 (1 H, m), 2.0 (1 H, m), 1.7-1.5
(4 H, m); 1.4-1.1 (12 H, m) 1.1 (1 H, t), 0.95 (3 H, t), 0.8 (9 H,
m). M.p. 145.degree.-147.degree. C. D.24.17 ##STR00443## Chemical
Name: 4-butylbenzamide, N-[(1S)-1- [[[(1R)-1-[3aS,aS,6S,7aR)-
hexahydro-3a,5,5-trimethyl- 4,6-methano,1,3,2-
benzodioxaborol-2-yl-]- 3-methylbutyl]amino]carbonyl]-
2-[(1H-tertazol-5-yl-acetylamino] ethyl]- Analytical Data: .sup.1H
NMR (DMSO-d6): 9 (1 H, s); 8.55 (1 H, d); 8.5 (1 H, br); 7.75 (2 H,
d); 7.3 (2 H, t); 4.6 (1 H, t); 3.4 (2 H, m); 2.65 (2 H, m); 2.2 (1
H, m); 2.1 (1 H, m); 1.8 (2 H, m); 1.6 (4 H, m); 1.3 (14 H, m);
0.9-0.80 (12 H, m). D.24.18 ##STR00444## Chemical Name:
4-butylbenzamide, N-[(1S)-1- [[[(1R)-1-[(3aS,aS,6S,7aR)-
hexahydro-3a,5,5-trimethyl- 4,6-methano-1,3,2-
benzodioxaborol-2-yl-]- 3-methylbutyl]amino]carbonyl]-2-
[(4-methysulfonylphenyl) carbonylamino]ethyl]- D.24.19 ##STR00445##
Chemical Name: Decanamide, N-[(1S)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro- 3a,5,5-trimethyl-4,6-methano-
1,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-2-
(nicotinonylamino)ethyl]- Analytical Data: .sup.1H NMR (DMSO-d6):
8.95 (1 H, s); 8.75 (1 H, m); 8.7 (1 H, d); 8.55 1 H, t), 8.15 (1
H, d); 8.0 (1 H, d); 7.50 (1 H, m); 4.6 (1 H, q); 4.1 (1 H, d); 3.5
(2 H, t); 2.62 (1 H, m); 2.2 (1 H, m); 2.10 (2 H, m); 2.08 (1 H,
m); 1.80 (2 H, m); 1.60 (2 H, m); 1.45 (2 H, m); 1.48 (3 H, m);
1.04 (22 H, m); 0.8 (12 H, m). D.24.20 ##STR00446## Chemical Name:
4-butylbenzamide, N-[(1S)-1- [[[(1R)-1-[(3aS,aS,6S,7aR)-
hexahydro-3a,5,5-trimethyl- 4,6-methano-1,3,2-
benzodioxaborol-2-yl-]- 3-methylbutyl]amino]carbonyl]-
2-[(4-(2H-tetrazol-5-yl)phenyl) carbonylamino]ethyl]- D.24.21
##STR00447## Chemical Name: 4-butylbenzamide, N-[(1S)-1-
[[[(1R)-1-[(3aS,aS,6S,7aR)- hexahydro-3a,5,5-trimethyl-
4,6-methano-1,3,2- benzodioxaborol-2-yl-]-
3-methylbutyl]amino]carbonyl]- 2-[(1-isoxazol-5-yl)-
carbonylamino]ethyl]- Analytical Data: .sup.1H NMR (DMSO-d6): 8.95
(1 H, t); 8.75 (1 H, m); 8.65 (2 H, m); 8.5 (2 H, d), 7.65 (2 H,
d); 7.3 (2 H, d); 7.05 (1 H, s); 4.7 (1 H, q); 4.1 (1 H, d); 3.65
(2 H, m); 2.82 (1 H, s); 2.65 (3 H, m); 2.2 (1 H, m); 2.10 (2 H,
m); 2.08 (1 H, m); 1.80 (2 H, m); 1.60 (4 H, m); 1.25 (12 H, m);
0.85 (12 H, m). M.p. 128.degree.-130.degree. C. D.24.22
##STR00448## Chemical Name: 4-butylbenzamide, N-[(1S)-1-
[[[(1R)-1-[(3aS,aS,6S,7aR)- hexahydro-3a,5,5-trimethyl-
4,6-methano-1,3,2- benzodioxaborol-2-yl-]-
3-methylbutyl]amino]carbonyl]- 2-[(4-cyanophenyl)
sulfonylamino]ethyl]- Analytical Data: .sup.1H NMR (DMSO-d6): 8.6
(1 H, d); 8.3 (1 H, d); 8.1 (1 H, t); 8.02 (2 H, d); 7.98 (2 H, d);
7.8 (2 H, d); 7,25 (2 H, d); 4.6 (1 H, t); 4.15 (1 H, d); 3.2 (2 H,
m); 2.2 (1 H, m); 2.1 (1 H, m); 1.8 (2 H, m); 1.6 (4 H, m); 1.3 (12
H, m); 0.9-0.80 (12 H, m). D.24.23 ##STR00449## Chemical Name:
4-butylbenzamide, N-[(1S)-1- [[[(1R)-1-[(3aS,aS,6S,7aR)-
hexahydro-3a,5,5-trimethyl- 4,6-methano-1,3,2-
benzodioxaborol-2-yl-]- 3-methylbulyl]amino]
carbonyl]-2-[(1-methyl- 1H-imidazole-4-) sulfonylamino]ethyl]-
Analytical Data: .sup.1H NMR (DMSO-d6): 8.61 (1 H, d); 8.25 (1 H,
d); 8.1 (1 H, t); 7.8 (2 H, d); 7.74 (2 H, d); 7.55 (1 H, br); 7.3
(2 H, d); 4.6 (1 H, t); 4.15 (1 H, d); 3.25 (2 H, m); 2.65 (3 H,
m); 2.2 (1 H, m); 2.04 (1 H, m); 1.8 (2 H, m); 1.6 (4 H, m); 1.3
(12 H, m); 0.9-0.80 (12 H, m). M.p. 69.degree.-71.degree. C.
D.24.24 ##STR00450## Chemical Name: 4-butylbenzamide, N-[(1S)-1-
[[[(1R)-1-[(3aS,aS,6S,7aR)- hexahydro-3a,5,5-trimethyl-
4,6-methano-1,3,2- benzodioxaborol-2-yl-]-
3-methylbutyl]amino]carbonyl]- 2-[(2-thiophene)
sulfonylamino]ethyl]- D.24.25 ##STR00451## Chemical Name:
4-butylbenzamide, N-[(1S)-1- [[[(1R)-1-[(3aS,aS,6S,7aR)-
hexahydro-3a,5,5-trimethyl- 4,6-methano-1,3,2-
benzodioxaborol-2-yl-]- 3-methylbutyl]amino]carbonyl]-
2-(6-morpholin-4- nicotinoylamino)ethyl]- D.24.26 ##STR00452##
Chemical Name: 4-butylbenzamide, N-[(1S)-1-
[[[(1R)-1-[(3aS,aS,6S,7aR)- hexahydro-3a,5,5-trimethyl-
4,6-methano-1,3,2- benzodioxaborol-2-yl-]- 3-methylbutyl]amino]
carbonyl]-2-(2-pyridin- 4-thiazolecarbonylamino)ethyl]- D.24.27
##STR00453## Chemical Name: 4-butylbenzamide, N-[(1S)-1-
[[[(1R)-1-[(3aS,aS,6S,7aR)- hexahydro-3a,5,5-trimethyl-
4,6-methano-1,3,2- benzodioxaborol-2-yl-]-
3-methylbutyl]amino]carbonyl]- 2-(4-methylphenyluriedo-
sulfonylamino)ethyl]- Analytical Data: .sup.1H NMR (DMSO-d6): 10 (1
H, br); 8.8 (1 H, s); 8.4 (2 H, d); 7.8 (2 H, d); 7.3 (2 H, d);
7.25 (2 H, d); 4.6 (1 H, t); 4.2 (1 H, d); 2.65 (3 H, m); 2.2 (4 H,
m); 2.0 (1 H, m); 1.8 (2 H, m); 1.6 (4 H, m); 1.3 (12 H, m);
0.9-0.80 (12 H, m). D.24.28 ##STR00454## Chemical Name:
4-phenoxybenzamide, N-[(1S)-1- [[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl- 4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-2-
[(benzyloxycarbonylamide) ethyl]- Analytical Data: .sup.1H NMR
(DMSO-d6): 8.78 (1 H, br); 8.4 (1 H, d); 7.9 (2, d); 7.45 (2 H, t);
7.3 (6 H, m); 7.21 (2 H, m); 7.05 (4 H, m); 5.0 (2 H, q); 4.7 (1 H,
t); 4.1 (1 H, d); 3.4 (2 H, m); 2.6 (1 H, m); 2.2 (4 H, m); 2.0 (1
H, m); 1.8 (2 H, m); 1.65 (2 H, m); 1.3 (9 H, m); 0.9-0.80 (9 H,
m). M.p. 100.degree.-103.degree. C. D.24.29 ##STR00455## Chemical
Name: 4-phenoxybenzamide, N-[(1S)-1- [[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl- 4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]- 2-[4-fluoro-
benzenesulfonammide]ethyl]- Analytical Data: .sup.1H NMR (DMSO-d6):
8.6 (1H, br); 8.35 (1 H, d); 7.9 (5 H, m); 7.45 (4 H, m);
7.2 (1 H, m); 7.05 (4 H, m); 4.6 (1 H, q); 4.1 (1 H, d); 3.1 (2 H,
m); 2.6 (1 H, m); 2.2 (4 H, m); 2.0 (1 H, m); 1.8 (2 H, m); 1.65 (2
H, m); 1.3 (9 H, m); 0.9-0.80 (9 H, m). M.p. 90.degree.-93.degree.
C. D.24.30 ##STR00456## Chemical Name: 4-phenoxybenzamide,
N-[(1S)-1- [[[(1R)-1-[(3aS,aS,6S,7aR)- hexahydro-3a,5,5-trimethyl-
4,6-methano-1,3,2- benzodioxaborol-2-yl-]-
3-methylbutyl]amino]carbonyl]-2- [(2,5-dimethyl-2H-pyrazole)
carbonylamino]ethyl]- Analytical Data: .sup.1H NMR (DMSO-d6): 8.9
(1 H, br); 8.55 (1 H, d); 8.48 (1 H, m); 7.9 (2 H, m); 7.48 (2 H,
m); 7.2 (1 H, m); 7.05 (4 H, m); 6.55 (1 H, s); 4.75 (1 H, q);
4.1(1 H, d); 3.6 (2 H, m); 2.2 (4 H, m); 2.1 (3 H, s); 2.0 (1 H,
m); 1.8 (2 H, m); 1.65 (2 H, m); 1.25 (9 H, m); 0.8 (9 H, m). M.p.
100.degree.-103.degree. C. D.24.31 ##STR00457## Chemical Name:
4-phenoxybenzamide, N-[(1S)-1- [[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl- 4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-
2-(4-phenylbenzoylamino)ethyl]- Analytical Data: .sup.1H NMR
(DMSO-d6): 8.85 (1 H, br); 8.55 (2 H, m); 7.9 (4 H, d); 7.75 (4 H,
m); 7.48 (5 H, m); 7.2 (1 H, t); 7.05 (4 H, m); 4.8 (1 H, q); 4.1
(1 H, d); 3.7 (2 H, m); 2.65 (1 H, m); 2.2 (1 H, m); 2.0 (1 H, m);
1.8 (2 H, m); 1.6 (2 H, m); 1.25 (9 H, m); 0.8 (9 H, m). M.p.
150.degree.-152.degree. C. D.24.32 ##STR00458## Chemical Name:
4-butylbenzamide, N-[(1S)-1- [[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl- 4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-2-
(4-phenylbenzoylamino)ethyl]- Analytical Data: .sup.1H NMR
(DMSO-d6): 8.85 (1 H, br); 8.6 (1 H, m); 8.5 (1 H, d); 7.9 (2 H,
m); 7.75 (5 H, m); 7.5 (2 H, t); 7.4 (1 H, m); 7.3 (2 H, m); 4.8 (1
H, q); 4.1 (1 H, d); 3.7 (2 H, m); 2.6 (3 H, m); 2.2 (1 H, m); 2.0
(1 H, m); 1.8 (2 H, m); 1.6 (4 H, m); 1.25 (9 H, m); 0.8 (12 H, m).
M.p. 195.degree.-198.degree. C. D.24.33 ##STR00459## Chemical Name:
4-butylbenzamide, N-[(1S)-1- [[[(1R)-1-[(3aS,4S,6S,7aR)-
hexahydro-3a,5,5-trimethyl- 4,6-methano-1,3,2-
benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-2-
(3-phenylpropynoylamino)ethyl]- Analytical Data: .sup.1H NMR
(DMSO-d6): 8.85 (1 H, m); 8.7 (1 H, m); 8.42 (1, d); 7.8 (2 H, m);
7.5 (5 H, m); 7.3 (3 H, m); 4.7 (1 H, q); 4.1 (1 H, d); 3.55 (2 H,
m); 2.85 (2, m); 2.65 (4 H, m); 2.2 (1 H, m); 2.0 (1 H, m); 1.8 (2
H, m); 1.6 (6 H, m); 1.25 (12 H, m); 0.8 (12 H, m). M.p.
118.degree.-120.degree. C. D.24.34 ##STR00460## Chemical Name:
4-butylbenzamide, N-[(1S)-1- [[[(1R)-1-[(3aS,aS,6S,7aR)-
hexahydro-3a,5,5-trimethyl- 4,6-methano-1,3,2-
benzodioxaborol-2-yl-]- 3-methylbutyl]amino]carbonyl]-
2-(2-hydroxy-3-nicotinoylamino) ethyl]- D.24.35 ##STR00461##
Chemical Name: 4-butylbenzamide, N-[(1S)-1-
[[[(1R)-1-[(3aS,aS,6S,7aR)- hexahydro-3a,5,5-trimethyl-
4,6-methano-1,3,2- benzodioxaborol-2-yl-]-3-
methylbutyl]amino]carbonyl]- 2-(D-piroglutamoylamino)ethyl]-
Analytical Data: .sup.1H NMR (DMSO-d6): 9.85 (1 H, d); 8.3 (1 H,
d); 8.1 (1 H, t); 7.8 (3 H, m); 7.3 (2 H, d); 4.7 (1 H, t); 4.15 (1
H, d); 3.9 (1 H, m); 3.5 (2 H, m); 2.65 (3 H, m); 2.2 (2 H, m); 2.0
(3 H, m); 1.8 (3 H, m); 1.6 (4 H, m); 1.3 (11 H, m); 0.9-0.80 (12
H, m). D.24.36 ##STR00462## Chemical Name: 4-butylbenzamide,
N-[(1S)-1- [[[(1R)-1-[(3aS,aS,6S,7aR)- hexahydro-3a,5,5-trimethyl-
4,6-methano-1,3,2- benzodioxaborol-2-yl-]-3-
methylbutyl]amino]carbonyl]- 2-(1-methanesulfonyl-
piperidine-4-carbonylamino) ethyl]- Analytical Data: .sup.1H NMR
(DMSO-d6): 9.9 (1 H, d); 8.4 (1 H, d); 8.0 (1 H, t); 7.75 (2 H, d);
7.3 (2 H, d); 4.68 (1 H, q); 4.15 (1 H, d); 3.5 (4 H, m); 2.8 (3 H,
s); 2.65 (3, m); 2.2 (2 H, m); 2.0 (1 H, m); 1.9-1.5 (10 H, m); 1.3
(12 H, m); 0.9-0.80 (12 H, m). M.p. 170.degree.-172.degree. C.
D.24.37 ##STR00463## Chemical Name: Decanamide, N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)- hexahydro-3a,5,5-trimethyl-
4,6-methano-1,3,2- benzodioxaborol-2-yl]-3-
methylbutyl]amino]carbonyl]-2- (3-phenyl-ureido)ethyl]- D.24.38
##STR00464## Chemical Name: Decanamide, N-[(1S)-1-
[[[(1R)-1-[(3aS,aS,6S,7aR)- hexahydro-3a,5,5-trimethyl-
4,6-methano-1,3,2- benzodioxaborol-2-yl-]-3-
methylbutyl]amino]carbonyl]-2- (acetamido)ethyl]-
Example D.25
Synthesis of Further Compounds
[0610] Following the procedures of Example D17, the following
compounds can be prepared starting from the compounds of Example
D.16.8 and D.16.9.
TABLE-US-00019 TABLE D-25 Chemical Name and Ex # Structure
Analytical Data D.25.1 ##STR00465## Chemical Name: Decanamide,
N-[(1S)-1-[[[(1R)- 1-[(3aS,aS,6S,7aR)-hexahydro-
3a,5,5-trimethyl-4,6-methano- 1,3,2-benzodioxaborol-2-yl-]-
3-methylbutyl]amino]carbonyl]- 2-amino]ethyl]-hydrochloride salt
Analytical Data: .sup.1H NMR (DMSO-d6): 8.4 (1H, d); 8.25 (1H, d);
8.15 (3H, br s); 4.58 (1H, m); 4.2 (1H, m); 3.1 ( H, m); 2.9 (1H,
m); 2.8 (1H, m); 2.4 (4H, m); 1.9 (1H, m); 1.85 (1H, m); 1.65 (2H,
m); 1.50 (2H, m); 1.35 (1H, m); 0.85 (12H, m). D.25.2 ##STR00466##
Chemical Name: 4-phenoxybenzamide, N-[(1S)-1-
[[[(1R)-1-[(3aS,4S,6S,7aR)-hexa- hydro-3a,5,5-trimethyl-4,6-
methano-1,3,2-benzodioxaborol- 2-yl]-3-methylbutyl]amino]
carbonyl]-2-(amino)ethyl]- hydrochloride salt Analytical Data:
.sup.1H NMR (DMSO-d6): 8.72 (1H, d); 8.54 (1H, d); 7.45 (2H, t);
7.22 (1H, t); 7.05 (4H, m); 4.8 (1H, m); 4.21 (1H, d); 3.25 (1H,
m); 3.15 (1H, m); 2.8 (1H, m); 2.25 (1H, m); 2.05 (1H, m); 1.9 (1H,
t); 1.82 (1H, m); 1.65 (2H, m); 1.28 (3H, s); 1.22 (3H, s); 0.85
(9H, m).
Example D.26
4-Butylbenzamide,
N-[(1R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-metha-
no-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-[(4-methylb-
enzoyl)amino]ethyl]-
##STR00467##
[0612] Following the same procedures used for the preparation of
the compound of Example D.17, the intermediate 4-butylbenzamide,
N-[(1R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-metha-
no-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-(aminoethyl-
)-hydrochloride salt is prepared using D-asparagine as starting
material. This latter intermediate is then reacted with
4-methylbenzoic acid following the procedure described in Example
D.18 to give the title compound.
[0613] .sup.1H NMR (MeOD-d4): 8.88 (2H, d); 8.45 (2H, m); 7.8 (2H,
d); 7.7 (2H, d); 7.35 (2H, m); 7.25 (2H, d); 4.75 (1H, m); 4.1 (1H,
d); 3.8 (1H, m); 3.65 (2H, m); 2.65 (3H, m); 2.2 (1H, m); 2.1 (1H,
m); 1.8 (2H, m); 1.6 (4H, m); 1.3-1.1 (2H, m); 0.9-0.80 (14H,
m).
Example E.1
Boronic acid,
[(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(2-naphthoyl)amino]--
1-oxopentyl]amino]-3-methylbutyl]-
##STR00468##
[0615] A mixture of naphthalene-2-carboxamide,
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-metha-
no-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]-amino]carbonyl]-4-[[imino(ni-
troamino)methyl]amino]butyl]- of Example D.1.1 (564 mg, 0.90 mmol),
2-methylpropylboronic acid (222 mg, 2.19 mmol) and 4N hydrogen
chloride dioxane solution (225 .mu.l) in a 40:60 heterogeneous
mixture of methanol:hexane (10 ml) was stirred at room temperature
for 4 hours. Hexane (4 ml) was added, the mixture was stirred for a
while, then the hexane layer was removed. Fresh hexane (5 ml) and
2-methylpropylboronic acid (100 mg, 0.99 mmol) were added and the
mixture was stirred at room temperature for 3 hours. The hexane
layer was removed and the methanol phase was washed with hexane
(2.times.5 ml). The residue obtained upon concentration of the
methanol phase was purified by silica gel column chromatography
eluting with ethyl acetate first, then with 40:40:20
acetone:methanol:hexane mixture. The product was redissolved in a
mixture of ethyl acetate (250 ml) and methanol (6 ml) and the
organic phase was washed with water (2.times.25 ml), dried over
sodium sulfate and concentrated. The residue was dried under vacuum
at 80.degree. C. for 3 hours affording the product as a white solid
(280 mg, 64% yield). M.p. 170-190.degree. C.
[0616] .sup.1H NMR (DMSO-d.sub.6): 8.76 (1H, m); 8.51 (2H, br);
8.09-7.09 (5H, m); 7.88 (2H, br); 7.60 (2H, br); 4.67 (1H, m); 3.17
(2H, m); 2.58 (1H, m); 1.81 (2H, m); 1.56 (3H, m); 1.38-1.11 (4H,
m); 0.83 (1H, m); 0.81 (1H, m); 0.74 (3H, d, J=6.4); 0.74 (3H, d,
J=6.4).
TABLE-US-00020 El. Anal. Calculated: C 54.33% H 6.43% N 17.28% B
2.22% Found C 54.87% H 6.64% N 17.00% B 2.12%
[0617] Further compounds prepared fundamentally in accordance with
the above experimental procedures are reported in Table E-1.
TABLE-US-00021 TABLE E-1 Ex # Structure Chemical Name and
Analytical Data E.1.1 ##STR00469## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-2-[((2E)-3-
ethoxycarbonyl-1-oxoprop-2-enyl)amino]-1-
oxopentyl]amino]-3-methylbutyl] Analytical Data: .sup.1H-NMR
(MeOH-d4): 7.07 (1H, d, J = 15.6 Hz); 6.74 (1H, d, J = 15.6 Hz);
4.64 (1H, dd, J = 6.3, 8.1); 4.25 (2H, q, J = 7.1); 2.75 (1H, t, J
= 7.4); 2.0-1.6 (5H, m); 1.34 (2H, m); 1.31 (3H, t, J = 7.1); 0.92
(6H, d, J = 6.6). E.1.2 ##STR00470## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-2-[(2-pyrazine-
carbonyl)amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data:
1H-NMR (DMSO-d6): 9.18 (1H, br); 8.96 (1H, d, J = 8.2; 8.87 (1H, d,
J = 2.4 Hz); 8.76 (2H, m); 8.51 (1H, br); 8.3-7.5 (2H, br); 4.63
(1H, m); 3.13 (2H, m); 2.53 (1H, m); 1.9-1.1 (7H, m); 0.73 (6H, d,
J = 6.6). E.1.3 ##STR00471## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-2-[(4-butyl-
benzoyl)amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data:
1H-NMR (DMSO-d6): 8.68 (1H, d, J = 2.5 Hz); 8.51 (1H, br); 8.48
(1H, d, J = 7.8 Hz); 8.3-7.5 (2H, br); 7.80 (2H, d, J = 8.1); 7.27
(2H, d, J = 8.1 Hz); 4.59 (1H, m); 3.15 (2H, m); 2.61 (2H, t, J =
7.7); 2.54 (1H, m); 1.9-1.1 (11H, m); 0.89 (3H, t, J = 7.3); 0.77
(3H, t, J = 6.8); 0.74 (6H, d, J = 6.6). E.1.4 ##STR00472##
Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[(2-naphthoyl)
amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data: 1H-NMR
(DMSO-d6): 8.77 (1H, br); 8.76 (1H, d, J = 8.0); 8.51 (1H, br);
8.50 (1H, s); 8.0 (4H, m); 8.3- 7.5 (2H, br); 7.6 (2H, m); 4.67
(1H, m); 3.17 (2H, m); 2.57 (1H, m); 1.9-1.1 (7H, m); 0.73 (6H, d,
J = 6.6). E.1.5 ##STR00473## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-2-[(3-(1,3-
dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-
propylamino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data:
1H-NMR (DMSO-d6): 8.59 (1H, br); 8.43 (1H, br); 8.27 (1H, d, J =
7.9 Hz); 7.82 (4H, m); 8.2-7.5 (2H, br); 4.31 (1H, m); 3.77 (2H,
m); 3.08 (2H, m); 2.51 (3H, m); 1.7-1.1 (7H, m); 0.78 (6H, m).
E.1.6 ##STR00474## Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[[2-(2-
methoxyethoxy)acetyl]amino]-1-oxopentyl]amino]- 3-methylbutyl], HCl
salt Analytical Data: 1H-NMR (MeOH-d4): 4.65 (1H, dd, J = 6.1, 8.6
Hz); 4.04 (2H, s); 3.70 (2H, m); 3.60 (2H, t, J = 4.04) 3.42 (3H,
s); 3.30 (2H, t, J = 6.9); 2.75 (1H, t, J = 7.5); 2.0-1.6 (5H, m);
1.34 (2H, m); 0.92 (6H, d, J = 6.6). E.1.7 ##STR00475## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-[[imino
(nitroamino)methyl]amino]-2-[(2-butoxyacetyl)
amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data: 1H-NMR
(MeOH-d4): 4.65 (1H, dd, J = 6.1, 8.6 Hz), 3.98 (2H, s); 3.54 (2H,
t, J = 6.6); 3.28 (2H, t, J = 6.9); 2.77 (1H, t, J = 7.6); 2.0-1.3
(11H, m); 0.95 (3H, t, J = 7.58); 0.92 (6H, d, J = 6.6). E.1.8
##STR00476## Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[[2-[2-(2-
methoxyethoxy)ethoxy]acetyl]amino]-1-
oxopentyl]amino]-3-methylbutyl] Analytical Data: 1H-NMR (MeOH-d4):
4.66 (1H, dd, J = 6.0, 8.8 Hz); 4.06 (2H, AB q, J = 15.7); 3.7 (6H,
m); 3.58 (2H, m); 3.37 (3H, s); 3.29 (2H, t, J = 6.9); 2.75 (1H, t,
J = 7.7); 2.0-1.6 (5H, m); 1.34 (2H, m); 0.92 (6H, d, J = 6.6).
E.1.9 ##STR00477## Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[[2-
(acetylamino)acetyl]amino]-1-oxopentyl] amino]-3-methylbutyl], HCl
salt Analytical Data: 1H-NMR (MeOH-d4): 4.61 (1H, dd, J = 5.7, 8.9
Hz); 3.86 (2H, s); 3.37 (3H, s); 3.30 (2H, t, J = 7.0); 2.75 (1H,
t, J = 7.7); 2.01 (3H, s); 2.0-1.6 (5H, m); 1.33 (2H, m); 0.92 (6H,
d, J = 6.6). E.1.10 ##STR00478## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-2-[[4-
(methoxycarbonyl)butanoyl]amino]-1- oxopentyl]amino]-3-methylbutyl]
Analytical Data: .sup.1H NMR (DMSO-d6): 8.50 (1H, br); 8.44 (1H, d,
J = 5.6 Hz); 8.17 (1H, d, J = 7.5); 7.92 (2H, br); 4.37 (1H, m);
3.58 (3H, s); 3.14 (2H, m); 2.57 (1H, m); 2.30 (2H, t, J = 7.3);
2.19 (2H, t, J = 7.5); 1.75 (2H, quint, J = 7.3); 1.71 (1H, br);
1.64-1.39 (4H, br); 1.23 (2H, m); 0.86 (2H, m); 0.82 (3H, d, J =
6.4); 0.81 (3H, d, J = 6.4). E.1.11 ##STR00479## Chemical Name:
Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[(2-
(naphthalen-2-yloxy)acetyl]amino]-1-
oxopentyl]amino]-3-methylbutyl] Analytical Data: .sup.1H NMR
(DMSO-d6): 8.81 (1H, br); 8.51 (1H, br); 8.40 (1H, d, J = 7.5 Hz);
7.88 (2H, br); 7.83 (2H, m); 7.75 (1H, m); 7.44 (1H, m); 7.35 (1H,
m); 7.26 (2H, m); 4.69 (2H, m); 4.51 (1H, m); 3.12 (2H, m); 2.60
(1H, m); 1.78 (1H, m); 1.73-1.39 (3H, m); 1.39- 1.11 (3H, m); 0.80
(6H, m). E.1.12 ##STR00480## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[(3-thiophen-2-yl-
propanoyl)amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data:
1H NMR (DMSO-d6): 8.65 (1H, br); 8.49 (1H, br); 8.20 (1H, d, J =
8.2 Hz); 7.86 (2H, br); 7.27 (1H, dd, J = 4.9, J = 0.9); 6.91 (1H,
dd, J = 5.1, J = 3.4); 6.84 (1H, m); 4.38 (1H, m); 3.11 (2H, m);
3.02 (2H, m); 2.56 (1H, m); 2.50 (2H, m); 1.69 (1H, m); 1.64-1.35
(4H, m); 1.27 (1H, m); 1.20 (1H, m); 0.82 (3H, d, J = 6.4); 0.81
(3H, d, J = 6.4). E.1.13 ##STR00481## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-2-[2-(2-
chlorophenyl)acetyl]amino]-3-methylbutyl] HCl salt Analytical Data:
.sup.1H NMR (DMSO-d6): 8.69 (1H, br); 8.51 (1H, br); 8.41 (1H, d, J
= 7.9 Hz); 7.87 (2H, br); 7.40 (1H, m); 7.32 (1H, m); 7.26 (2H, m);
4.42 (1H, m); 3.66 (2H, m); 3.14 (2H, m); 2.60 (1H, m); 1.73 (1H,
m); 1.68- 1.40 (4H, m); 1.26 (2H, m); 0.83 (3H, d, J = 6.4); 0.82
(3H, d, J = 6.4). E.1.14 ##STR00482## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-2-[(1-oxo-4-(1-
butylpiperidin-4-yl)butyl)amino]-1- oxopentyl]amino]-3-methylbutyl]
Analytical Data: .sup.1H NMR (DMSO-d6): 8.60 (1H, br); 8.50 (1H,
br); 8.10 (1H, br); 8.00 (2H, br); 4.36 (1H, m); 3.13 (2H, br);
2.86 (2H, br); 2.50 (1H, m); 2.27 (1H, br); 2.11 (2H, m); 1.76-1.34
(11H, m); 1.34-0.98 (11H, m); 0.87 (3H, t, J = 7.1 Hz), 0.82 (3H,
d, J = 6.4); 0.81 (3H, d, J = 6.4). E.1.15 ##STR00483## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[(1-
octanesulfonyl)amino]-1-oxopentyl]amino]-3- methylbutyl], HCl salt
Analytical Data: .sup.1H NMR (DMSO-d6): 8.80 (1H, br); 8.50 (1H,
br); 7.87 (2H, br); 7.52 (1H, d, J = 8.6 Hz); 3.92 (1H, m); 3.15
(2H, m); 2.94 (2H, t, J = 7.7); 2.62 (1H, m); 1.75-1.43 (7H, m);
1.38-1.31 (4H, m); 1.24 (8H, s); 0.92-0.75 (9H, m). E.1.16
##STR00484## Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-[(4-
methylbenzoyl)amino]-2-[(decanoylamino)]-1-
oxopropyl]amino]-3-methylbutyl] Analytical Data: .sup.1H NMR
(CD3OD): 7.73 (2H, d, J = 8.0 Hz); 7.28 (2H, d, J = 8.0); 4.78 (1H,
t, J = 6.5); 3.82 (1H, dd, J = 6.9, 13.5); 3.61 (1H, dd, J = 6.9,
13.5); 2.74 (1H, m); 2.39 (3H, s); 2.24 (2H, t, J = 7.4); 1.6-1.15
(17H, m); 0.89 (6H, m); 0.80 (3H, d, J = 6.5). E.1.17 ##STR00485##
Chemical Name: Boronic acid, [(1R)-1-[[(2S,3R)-3-hydroxy-2-
[(decanoyl)amino]-1-oxobutyl]amino]-3-methylbutyl] Analytical Data:
.sup.1H NMR (DMSO-d6): 8.58 (1H, br); 7.70 (1H, d, J = 8.6 Hz),
4.93 (1H, br); 4.31 (1H, dd, J = 4.0, 8.6); 3.96 (1H, m); 2.56 (1H,
m); 2.18 (2H, m); 1.60 (1H, m); 1.49 (2H, m); 1.35-1.15 (14H, m);
1.03 (3H, d, J = 6.4); 0.83 (9H, m). E.1.18 ##STR00486## Chemical
Name: Boronic acid, [(1R)-1-[[(2S,3R)-3-hydroxy-2-
[[10-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-
decanoyl]amino]-1-oxobutyl]amino]-3-methylbutyl] Analytical Data:
.sup.1H NMR (DMSO-d6): 8.55 (1H, br); 7.84 (4H, m); 7.69 (1H, d, J
= 8.4 Hz), 4.94 (1H, d, J = 5.4); 4.30 (1H, dd, J = 4.0, 8.6); 3.95
(1H, m); 3.55 (2H, m); 2.55 (1H, m); 2.17 (2H, m); 1.65-1.35 (5H,
m); 1.3- 1.1 (12H, m); 1.02 (3H, d, J = 6.4); 0.83 (9H, m).
[0618] Further compounds prepared according to the above procedure
for Example E.1 are reported in Table E-1A.
TABLE-US-00022 TABLE E-1A Ex # Structure Chemical Name and
Analytical Data E.1.19 ##STR00487## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-2-[((RS)-10-
cyano-2-cyclopentydecanoyl)amino]-1-
oxopentyl]amino]-3-methylbutyl] Analytical Data: 1H-NMR (MeOH-d4):
4.57 (1 H, m); 3.29 (2 H, m); 3.20 (2 H, m); 2.76 (1 H, t, J =
7.5Hz); 2.43 (2 H, t, J = 7.1); 2.05 (1 H, m); 2.0-1.1 (11 H, m);
0.93 (6 H, d, J = 6.6). E.1.20 ##STR00488## Chemical Name: Boronic
acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[(10-(1,3-
dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxodecyl]-)
amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data: 1H-NMR
(MeOH-d4): 7.82 (4 H, m); 4.52 (1 H, m); 3.66 (2 H, t, J = 7.3);
3.27 (2 H, m); 2.75 (1 H, m); 2.24 (2 H, t, J = 7.3 Hz); 1.9-1.2
(20 H, m); 0.91 (6 H, d, J = 6.6). E.1.21 ##STR00489## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[(2-
cyclopentyl-10-(1,3-dihydro-1,3-dioxo-2H-
isoindol-2-yl)-1-oxodecyl]-)amino]-1-
oxopentyl]amino]-3-methylbutyl] Analytical Data: 1H-NMR (MeOH-d4):
7.82 (4 H, m); 4.57 (1 H, m); 3.66 (2 H, t, J = 7.3); 3.28 (2 H,
m); 2.75 (1 H, m); 2.05 (1 H, m); 2.0-1.1 (30 H, m); 0.91 (6 H, two
d, J = 6.6). E.1.22 ##STR00490## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-2-[[7-
(methoxycarbonyl)heptanoyl]amino]-1-
oxopentyl]amino]-3-methylbutyl] Analytical Data: .sup.1H NMR
(DMSO-d6): 8.60 (1 H, d, J = 8.4 Hz); 8.50 (1 H, br); 8.06 (1 H, d,
J = 7.9); 7.92 (2 H, br); 4.36 (1 H, m); 3.58 (3 H, s); 3.13 (2 H,
m); 2.55 (1 H, m); 2.28 (2 H, t, J = 7.5); 2.12 (2 H, m); 1.69 (1
H, m); 1.49 (7 H, m); 1.24 (7 H, m); 0.81 (6 H, m).
[0619] Further compounds prepared according to the above procedure
for Example E.1 are reported in Table E-1B.
TABLE-US-00023 TABLE E-1B Ex # Structure Chemical Name and
Analytical Data E.1.23 ##STR00491## Chemical Name: Boronic acid,
[(1R)-1-[[(2S,3R)-3-hydroxy-2-[(4-
phenylbutanoyl)amino]-1-oxobutyl]amino]-3- methylbutyl]. Analytical
Data: .sup.1H NMR (MeOH-d4): 7.29-7.13 (5 H, m); 4.53 (1 H, d, J =
3.9); 4.21-4.14 (1 H, m); 2.72 (1 H, d, J = 7.6); 2.65 (2 H, t, J =
7.6); 2.34 (2 H, t, J = 7.5); 2.10-2.89 (2 H, m); 1.70-1.59 (1 H,
m); 1.37-1.27 (2 H, m); 1.21 (3 H, d, J = 6.4); 0.94-0.89 (6 H, m).
E.1.24 ##STR00492## Chemical Name: Boronic acid,
[(1R)-1-[[(2S,3R)-3-hydroxy-2-
[(undecylaminocarbonyl)amino]-1-oxobutyl]amino]-3- methylbutyl].
Analytical Data: .sup.1H NMR (MeOH-d4): 4.43 (1 H, d, J = 2.9);
4.27-4.20 (1 H, m); 3.16 (2 H, t, J = 6.9); 2.74 (1 H, t, J = 7.6);
1.76- 1.66 (1 H, m); 1.58-1.46 (3 H, m); 1.42-1.30 (26 H, m); 1.25
(3 H, d, J = 6.4). E.1.25 ##STR00493## Chemical Name: Boronic acid,
[(1R)-1-[[(2S,3R)-3-hydroxy-2-[(1-
Bromo-2-naphthoyl)amino]-1-oxobutyl]amino]-3- methylbutyl].
Analytical Data: .sup.1H NMR (MeOH-d4): 8.37 (1 H, d, J = 8.52);
7.99 (2 H, dd, J = 8.2, J = 13.0); 7.75-7.60 (2 H, m); 4.82 (1 H,
d, J = 4.19); 4.31-4.23 (1 H, m); 2.81 (1 H, dd, J = 6.10, J =
9.14); 1.77-1.64 (1 H, m); 1.48-1.38 (2 H, m); 1.36 (3 H, d, J =
6.38); 1.0-0.9 (6 H, m). E.1.26 ##STR00494## Chemical Name: Boronic
acid, [(1R)-1-[[(2S,3R)-3-hydroxy-2-[(6-
Bromo-2-naphthoyl)amino]-1-oxobutyl]amino]-3- methylbutyl].
Analytical Data: .sup.1H NMR (MeOH-d4): 8.49 (1 H, s); 8.17 (1 H,
d, J = 1.4); 7.99 (1 H, dd, J = 1.65, J = 8.66); 7.95 (2 H, dd, J =
2.70, J = 8.62); 7.69 (1 H, dd, J = 1.90, J = 8.77); 4.81 (1 H, d,
J = 4.26); 4.38-4.30 (1 H, m); 2.77 (1 H, t, J = 7.63); 1.71- 1.59
(1 H, m); 1.40-1.33 (2 H, m); 1.31 (3 H, d, J = 6.39); 0.94-0.90 (6
H, m).
[0620] Further compounds prepared according to the above procedure
for Example E.1 are reported in Table E-1C. starting from the
compounds of Example D.8.19 and D.8.20.
TABLE-US-00024 TABLE E-1C Ex # Structure Chemical Name and
Analytical Data E.1.27 ##STR00495## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-3-carbamoyl-2-
[(decanoyl)amino]-1-oxopropyl]amino]-3-methylbutyl] Analytical
Data: 1H-NMR (MeOH-d4): 4.76 (1 H, t, J = 6.0); 2.58-2.52 (3 H, m);
2.14-2.09 (2 H, m); 1.64-1.52 (1 H, m); 1.51- 1.40 (2 H, m);
1.30-1.12 (14 H, m); 0.84-0.80 (9 H, m). E.1.28 ##STR00496##
Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-carbamoyl-2-[4-
butyl(benzoyl)amino]-1-oxopropyl]amino]-3- methylbutyl] Analytical
Data: 1H-NMR (MeOH-d4): 7.78 (2 H, d, J = 8.24 Hz); 7.32 (2 H, d, J
= 8.22 Hz); 5.16 (1 H, T, J = 6.52); 2.91 (2 H, dd, J = 2.09 Hz, J
= 6.53 Hz); 2.78 (1 H, t, J = 7.59 Hz); 2.74- 2.66 (2 H, m);
1.72-1.60 (3 H, m); 1.44-1.30 (5 H, m); 1.00-0.9 (9 H, m).
[0621] Further compounds prepared according to the above procedure
for Example E.1 are reported in Table E-1D. starting from the
compounds of Example D.2.9 and D.2.10.
TABLE-US-00025 TABLE E-1D Ex # Structure Chemical Name and
Analytical Data E.1.29 ##STR00497## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-2-[(decanoyl)amino]-1-
oxo-5-ureido-pentyl]amino]-3-methylbutyl] Analytical Data: 1H-NMR
(DMSO-d6): 8.56 (1 H, s); 8.07 (1 H, d, J = 8.03 Hz); 5.96 (1 H, t,
J = 5.18 Hz); 5.38 (2 H, s); 4.42-4.20 (1 H, m); 3.01-2.85 (2 H,
m); 2.65-2.40 (1 H, m); 2.25-2.00 (2 H, m); 1.70-1.52 (2 H, m);
1.52-1.40 (3 H, m); 1.40-1.10 (16 H, m); 0.90-0.75 (9 H, m). E.1.30
##STR00498## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-2-[(4-butylbenzoyl)amino]-
1-oxo-5-ureido-pentyl]amino]-3-methylbutyl] Analytical Data: 1H-NMR
(MeOH-d4 + DMSO-d6): 7.80 (2 H, d, J = 8.08 Hz); 7.28 (2 H, d, J =
8.16 Hz); 4.58 (1 H, t, J = 7.41 Hz); 3.00 (2 H, t, J = 6.72 Hz);
2.63 (2 H, t, J = 7.64 Hz); 1.82- 1.74 (2 H, m); 1.68-1.52 (4 H,
m); 1.52-1.36 (2 H, m); 1.34-1.26 (2 H, m); 1.21 (2 H, t, J = 7.23
Hz); 0.89 (3 H, t, J = 7.35 Hz); 0.84 (6 H, d, J = 6.55 Hz).
Example E.2
Boronic acid,
[(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(decanoyl)amino]-1-o-
xopentyl]amino]-3-methylbutyl]
##STR00499##
[0623] Decanamide,
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-metha-
no-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-4-[[imino(nit-
roamino)methyl]amino]butyl]- of Example D.1 (77 mg, 0.12 mmol), was
dissolved in Et.sub.2O (1 mL) and HC137% (2 mL) was added carefully
at 0.degree. C. The reaction mixture was allowed to warm to room
temperature and to shake overnight. The mixture was concentrated to
dryness and the residue, dissolved in MeOH (1 mL), was passed
through ISOLUTE PSA cartridge, and washed with MeOH. The solvent
was evaporated and the reaction crude product was purified with
ISOLUTE SPE-DIOL cartridges (DCM:MeOH 1:1) to afford the title
compound (19 mg, yield 33%).
[0624] NMR (DMSO+D.sub.2O, 343 K): 4.20 (m, 1H); 3.13 (m, 2H); 3.05
(m, 1H); 2.10 (t, J=6.2 Hz, 2H); 1.69 (m, 1H); 1.53-1.40 (m, 4H);
1.39-1.20 (m, 14H); 0.84 (m, 9H).
[0625] LC-MS 468.9, MH+. ESI POS; AQA; spray 4 kV/skimmer:
20V/probe 250.degree. C.
[0626] Further compounds prepared fundamentally in accordance with
the above experimental procedures are reported in Table E-2.
TABLE-US-00026 TABLE E-2 Ex # Structure Chemical Name and
Analytical Data E.2.1 ##STR00500## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-2-[(1-
oxodecyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical Data:
MS: MH+ 468.9; 1H-NMR: (DMSO + D20, 343 K): 4.20 (m, 1 H); 3.13 (m,
2 H); 3.05 (m, 1 H); 2.10 (t, J = 6.2 Hz, 2 H); 1.69 (m, 1 H);
1.53-1.40 (m, 4 H); 1.39-1.20 (m, 14 H); 0.84 (m, 9 H). E.2.2
##STR00501## Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-
[(octanoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical
Data: MS: [M - 18]H+ 441.4 E.2.3 ##STR00502## Chemical Name:
Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[(1-
phenylcyclopentanecarbnyl)amino]-1- oxopentyl]amino]-3-methylbutyl]
Analytical Data: MS: [M - 18]H+ 487.0 E.2.4 ##STR00503## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[((2R)-2-
phenylbutanoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical
Data: MS: [M - 18]H+ 461.2 E.2.5 ##STR00504## Chemical Name:
Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[[4-(1,1-
Dimethylethyl)cyclohexanecarbonyl]amino]-1-
oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M - 18]H+
481.1 E.2.6 ##STR00505## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-2-[(trans-4-
pentylcyclohexanecarbonyl)amino]-1- oxopentyl]amino]-3-methylbutyl]
Analytical Data: MS: [M - 18]H+ 495.4 E.2.7 ##STR00506## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[(4-
phenylbutanoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical
Data: MS: [M - 18]H+ 461.4 E.2.8 ##STR00507## Chemical Name:
Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[(4-(1,1-
dimethylethyl)benzoyl)amino]-1-oxopentyl]amino]- 3-methylbutyl]
Analytical Data: MS: [M - 18]H+ 475.1 E.2.9 ##STR00508## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-
[(nonanoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical
Data: MS: [M - 18]H+ 455.1 E.2.10 ##STR00509## Chemical Name:
Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[(2-
thiophenecarbonyl)amino]-1-oxopentyl]amino]-3- methylbutyl]
Analytical Data: MS: [M - 18]H+ 425.3 E.2.11 ##STR00510## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[(2,3-
difluorobenzoyl)amino]-1-oxopentyl]amino]-3- methylbutyl]
Analytical Data: MS: [M - 18]H+ 455.0 E.2.12 ##STR00511## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-
[(dodecanoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical
Data: MS: [M - 18]H+ 497.2 E.2.13 ##STR00512## Chemical Name:
Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[[2-(2-
iodophenyl)acetyl]amino]-1-oxopentyl]amino]-3- methylbutyl]
Analytical Data: MS: [M - 18]H+ 558.9 E.2.14 ##STR00513## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2- [(cyclohexanecarbonyl)amino]-1-
oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M - 18]H+
425.0 E.2.15 ##STR00514## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-2-[(2-
methylbenzoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical
Data: MS: [M - 18]H+ 433.0 E.2.16 ##STR00515## Chemical Name:
Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[((2S)-2-
phenylpropanoyl)amino]-1-oxopentyl]amino]-3- methylbutyl]
Analytical Data: MS: [M - 18]H+ 447.3 E.2.17 ##STR00516## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[(2,2-
dimethylbutanoyl)amino]-1-oxopentyl]amino]-3- methylbutyl]
Analytical Data: MS: [M - 18]H+ 413.3 E.2.18 ##STR00517## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[(quinoline-2-
carbonyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical Data:
MS: [M - 18]H+ 470.0 E.2.19 ##STR00518## Chemical Name: Boronic
acid, [(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-2-[(non-2-
enoyl)amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data: MS:
[M - 18]H+ 453.1 E.2.20 ##STR00519## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-2-[(2-
methylcyclohexanecarbonyl)amino]-1- oxopentyl]amino]-3-methylbutyl]
Analytical Data: MS: [M - 18]H+ 439.4 E.2.21 ##STR00520## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[(hept-2-
enoyl)amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data: MS:
[M - 18]H+ 425.4 E.2.22 ##STR00521## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-2-[[2-(3,4-
dimethylphenoxy)acetyl]amino]-1- oxopentyl]amino]-3-methylbutyl]
Analytical Data: MS: [M - 18]H+ 477.3 E.2.23 ##STR00522## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[((RS)-4-
ethyloctanoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical
Data: MS: [M - 18]H+ 469.5 E.2.24 ##STR00523## Chemical Name:
Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[(hexahydro-
2,5-methanopentalene-3a(1H)-carbonyl)amino]-1-
oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M - 18]H+
463.5 E.2.25 ##STR00524## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-2-
[(bicyclo[2.2.1]heptane-2-carbonyl)amino]-1-
oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M - 18]H+
437.4 E.2.26 ##STR00525## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-2-[(5-
methylhexanoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical
Data: MS: [M - 18]H+ 427.0 E.2.27 ##STR00526## Chemical Name:
Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[(2,4-
dimethylthiazole-5-carbonyl)amino]-1-
oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M - 18]H+
454.3 E.2.28 ##STR00527## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-2-[(furan-3-
carbonyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical Data:
MS: [M - 18]H+ 408.8 E.2.29 ##STR00528## Chemical Name: Boronic
acid, [(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-2-[(2-
cycloheptylacetyl)amino]-1-oxopentyl]amino]-3- methylbutyl]
Analytical Data: MS: [M - 18]H+ 453.2 E.2.30 ##STR00529## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[(1-
methylcyclopropanecarbonyl)amino]-1-
oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M -
18]H+397.2 E.2.31 ##STR00530## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-2-[(3-
methylbutanoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical
Data: MS: [M - 18]H+ 399.4 E.2.32 ##STR00531## Chemical Name:
Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[(3-
phenylpropanoyl)amino]-1-oxopentyl]amino]-3- methylbutyl]
Analytical Data: MS: [M - 18]H+ 447.3 E.2.33 ##STR00532## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[[(E)-3-(3-
methylphenyl)acryl]amino]-1-oxopentyl]amino]-3- methylbutyl]
Analytical Data: MS: [M - 18]H+ 459.5 E.2.34 ##STR00533## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[(2-
adamantan-1-ylacetyl)amino]-1-oxopentyl] 3-methylbutyl] Analytical
Data: MS: [M - 18]H+ 491.2 E.2.35 ##STR00534## Chemical Name:
Boronic acid, [(1R)-1-[[(2S)-5-
[[immo(nitroamino)methyl]amino]-2-[((RS)-2-
methylbutanoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical
Data: MS: [M - 18]H+ 398.9 E.2.36 ##STR00535## Chemical Name:
Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[(2-
phenylacetyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical
Data: MS: [M - 18]H+ 433.4 E.2.37 ##STR00536## Chemical Name:
Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[[2-(4-
methoxyphenyl)acetyl]amino]-1-oxopentyl]amino]- 3-methylbutyl]
Analytical Data: MS: [M - 18]H+ 463.5 E.2.38 ##STR00537## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[[2-(4-
bromophenyl)acetyl]amino]-1-oxopentyl]amino]-3- methylbutyl]
Analytical Data: MS: [M - 18]H+511.3 E.2.39 ##STR00538## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[((RS)-4-
methyloctanoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical
Data: MS: [M - 18]H+ 455.0 E.2.40 ##STR00539## Chemical Name:
Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[(2-fluoro-5-
methylbenzoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical
Data: MS: [M - 18]H+ 451.4 E.2.41 ##STR00540## Chemical Name:
Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[[2-
(bicyclo[2.2.1]hept-2-yl)acetyl]amino]-1-
oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M - 18]H+
451.0 E.2.42 ##STR00541## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-2-[(4-
phenoxybutanoyl)amino]-1-oxopentyl]amino]-3- methylbutyl]
Analytical Data: MS: [M - 18]H+ 477.4 E.2.43 ##STR00542## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[(2-
pyridinecarbonyl)ammo]-1-oxopentyl]amino]-3- methylbutyl]
Analytical Data: MS: [M - 18]H+ 419.9 E.2.44 ##STR00543## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[(3-
pyridinecarbonyl)amino]-1-oxopentyl]amino]-3- methylbutyl]
Analytical Data: MS: [M - 18]H+ 420.3 E.2.45 ##STR00544## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-
[(tridecanoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical
Data: MS: [M - 18]H+ 511.6 E.2.46 ##STR00545## Chemical Name:
Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[(8-
phenyloctanoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical
Data: MS: [M - 18]H+ 517.3 E.2.47 ##STR00546## Chemical Name:
Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[[4-(4-
methanesulfonylphenyl)-4-oxobutanoyl]amino]-1-
oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M - 18]H+
553.3 E.2.48 ##STR00547## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-2-[[3-
(naphthalen-2-ylsulfanyl)-propanoyl]amino]-1-
oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M - 18]H+
529.3 E.2.49 ##STR00548## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-2-[[2-
[(phenylmethyl)sulfanyl]acetyl]amino]-1-
oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M - 18]H+
479.5
E.2.50 ##STR00549## Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[(3-
Methylsulfanylpropanoyl)amino]-1- oxopentyl]amino]-3-methylbutyl]
Analytical Data: MS: [M - 18]H+ 416.9 E.2.51 ##STR00550## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[((2S)-1-
acetylpyrrolidine-2-carbonyl)amino]-1-
oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M - 18]H+
454.1 E.2.52 ##STR00551## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-2-[[trans-3-(2-
bromophenyl)acryl]amino]-1-oxopentyl]amino]-3- methylbutyl]
Analytical Data: MS: [M - 18]H+ 523.0 E.2.53 ##STR00552## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[[2-(tetrazol-
1-yl)acetyl]amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical
Data: MS: [M - 18]H+ 425.0 E.2.54 ##STR00553## Chemical Name:
Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[[2-
(pyrimidin-2-ylsulfanyl)acetyl]amino]-1-
oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M - 18]H+
467.0 E.2.55 ##STR00554## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-2-[[2-(4-
ethylphenoxy)acetyl]amino]-1-oxopentyl]amino]-3- methylbutyl]
Analytical Data: MS: [M - 18]H+ 476.9 E.2.56 ##STR00555## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[[2-(2,5-
dimethylphenyl)acetyl]amino]-1-oxopentyl]amino]- 3-methylbutyl]
Analytical Data: MS: [M - 18]H+ 461.4 E.2.57 ##STR00556## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[(8-oxo-8-
phenyloctanoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical
Data: MS: [M - 18]H+ 531.0 E.2.58 ##STR00557## Chemical Name:
Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[[2-(2-
naphthylsulfanyl)acetyl]amino]-1- oxopentyl]amino]-3-methylbutyl]
Analytical Data: MS: [M - 18]H+ 515.6 E.2.59 ##STR00558## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[[(RS)-2-
cyclopentylhexanoyl]amino]-1-oxopentyl]amino]- 3-methylbutyl]
Analytical Data: MS: [M - 18]H+ 481.1 E.2.60 ##STR00559## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[[3-(4-
methylphenyl)acryl]amino]-1-oxopentyl]amino]-3- methylbutyl]
Analytical Data: MS: [M - 18]H+ 459.0 E.2.61 ##STR00560## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[[4-(4-
methoxyphenyl)-butanoyl]amino]-1- oxopentyl]amino]-3-methylbutyl]
Analytical Data: MS: [M - 18]H+ 491.6 E.2.62 ##STR00561## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[(2-thiophen-
3-yl-acetyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical
Data: MS: [M - 18]H+ 438.9 E.2.63 ##STR00562## Chemical Name:
Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[[2-
(dimethylamino)acetyl]amino]-1- oxopentyl]amino]-3-methylbutyl]
Analytical Data: MS: [M - 18]H+ 400.2 E.2.64 ##STR00563## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[[5-oxo-5-
(thiophen-3-yl)pentanoyl]amino]-1- oxopentyl]amino]-3-methylbutyl]
Analytical Data: MS: [M - 18]H+ 494.9 E.2.65 ##STR00564## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-
[(acetyl)amino]-1-oxopentyl]amino]-3-methylbutyl] Analytical Data:
MS: [M - 18]H+ 357.2 E.2.66 ##STR00565## Chemical Name: Boronic
acid, [(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-2-[(2-
ethylsulfanylacetyl)amino]-1-oxopentyl]amino]-3- methylbutyl]
Analytical Data: MS: [M - 18]H+ 417.4 E.2.67 ##STR00566## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[(10-
hydroxydecanoyl)amino]-1-oxopentyl]amino]-3- methylbutyl]
Analytical Data: MS: [M - 2H2O]H+ 467.0 E.2.68 ##STR00567##
Chemical Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[(2-
methylsulfanylacetyl)amino]-1-oxopentyl]amino]- 3-methylbutyl]
Analytical Data: MS: [M - 18]H+ 402.9 E.2.69 ##STR00568## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[[(thiophene-
2-sulfonyl)acetyl]amino]-1-oxopentyl]amino]-3- methylbutyl]
Analytical Data: MS: [M - 18]H+ 503.1 E.2.70 ##STR00569## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[[3-
(benzenesulfonyl)propanoyl]amino]-1-
oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M - 18]H+
510.9 E.2.71 ##STR00570## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-2-[[(RS)-
tetrahydrofuran-3-carbonyl]amino]-1-
oxopentyl]amino]-3-methylbutyl] Analytical Data: MS: [M - 18]H+
413.2 E.2.72 ##STR00571## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-2-
[(naphthalene-1-sulfonyl)amino]-1- oxopentyl]amino]-3-methylbutyl]-
Analytical Data: MS: [M - 18]H+ 505.23 E.2.73 ##STR00572## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-
[(naphthalene-2-sulfonyl)amino]-1- oxopentyl]amino]-3-methylbutyl]-
Analytical Data: MS: [M - 18]H+ 505.49
[0627] Further compounds prepared according to the above procedure
for Example E.2 are reported in Table E-2A.
TABLE-US-00027 TABLE E-2A Ex # Structure Chemical Name and
Analytical Data E.2.75 ##STR00573## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-5- [[imino(nitroamino)methyl]amino]-2-[[6-
(acetylamino)hexanoyl]amino]-1- oxopentyl]amino]-3-methylbutyl]
Analytical Data: MS: [M - 18]H+ 470.2 E.2.76 ##STR00574## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[[(RS)-2-(4-
chlorophenyl)propanoyl]amino]-1- oxopcntyl]amino]-3-methylbutyl]
Analytical Data: MS: [M - 18]H+ 481.1 E.2.77 ##STR00575## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[[2-(4-
bromophenoxy)acetyl]amino]-1-oxopentyl]amino]- 3-methylbutyl]
Analytical Data: MS: [M - 18]H+ 524.1 E.2.78 ##STR00576## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[[3-(4-
ethylphenyl)propanoyl]amino]-1- oxopentyl]amino]-3-methylbutyl]
Analytical Data: MS: [M - 18]H+ 475.2 E.2.79 ##STR00577## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[3-[4-
(heptyloxy)phenyl]-ureido]-1-oxopentyl]amino]-3- methylbutyl]
Analytical Data: MS: [M - 18]H+ 548.3 E.2.80 ##STR00578## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[(5-
oxohexanoyl)amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical
Data: MS: [M - 18]H+ 427.2 E.2.81 ##STR00579## Chemical Name:
Boronic acid, [(1R)-1-[[(2S)-5-
[[imino(nitroamino)methyl]amino]-2-[[(2RS)-1-
[(1,1-dimethylethoxy)carbonyl]piperidine-2-
carbonyl]amino]-1-oxopentyl]amino]-3- methylbutyl] Analytical Data:
MS: [M - 18]H+ 526.2
Example E.3
Boronic acid,
[(1R)-1-[[(2S,3R)-3-hydroxy-2-[(4-butylbenzoyl)amino]-1-oxobutyl]amino]-3-
-methylbutyl]
##STR00580##
[0629] A mixture of 4-butylbenzamide,
N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-me-
thano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]-carbonyl]-2-hydroxy-
propyl]- of Example D.3.179 (1.38 g, 2.63 mmol),
2-methylpropylboronic acid (0.75 g, 7.37 mmol) and 2N aqueous
hydrochloric acid (2 ml) in a heterogeneous mixture of methanol (20
ml) and hexane (20 ml) was stirred at room temperature for 16
hours. The mixture was diluted with methanol (20 ml) and hexane (20
ml) then the hexane layer was removed. Ethyl acetate (50 ml) was
added to the methanol layer which was then concentrated. The
residue was taken up with ethyl acetate and the mixture was
concentrated. This step was repeated (2-3 times) until an amorphous
white solid was obtained. The solid was then triturated with
diethyl ether (10-15 ml) and the surnatant was removed by
decantation. This step was repeated 4 times. After a further
trituration with diethyl ether (15 ml) the white solid was
collected by filtration and dried under vacuum at room temperature
(0.724 g, 70% yield).
[0630] .sup.1H NMR (MeOH-d4): 7.83 (2H, d, J=8.2); 7.34 (2H, d,
J=8.2); 4.77 (1H, d, J=6.4); 4.36-4.28 (1H, m); 2.77 (1H, t,
J=7.6); 2.71 (2H, t, J=7.6); 1.72-1.58 (3H, m); 1.46-1.32 (4H, m);
1.29 (3H, d, J=6.4); 0.97 (3H, t, J=7.34); 0.94 (6H, dd, J=1.1,
6.6)
[0631] Further compounds prepared according to the above procedure
for Example E.3 are reported in Table E-3.
TABLE-US-00028 TABLE E-3 Ex # Structure Chemical Name and
Analytical Data E.3.1 ##STR00581## Chemical Name: Boronic acid,
[(1R)-1-[[(2S,3R)-3-hydroxy-2-[(2-
naphthoyl)amino]-1-oxobutyl]amino]-3-methylbutyl]. Analytical Data:
.sup.1H NMR (MeOH-d4): 8.51 (1 H, s); 8.10-7.95 (4 H, m); 7.66-7.58
(1 H, m); 4.84 (1 H, d, J = 4.1); 4.42-4.33 (1 H, m); 2.77 (1 H, t,
J = 7.6); 1.75-1.62 (1 H, m); 1.41-1.36 (2 H, m); 1.34 (3 H, d, J =
6.4); 0.94 (6 H, d, J = 6.5). E.3.2 ##STR00582## Chemical Name:
Boronic acid, [(1R)-1-[[(2S,3R)-3-hydroxy-2-[(p-
tolyloxyacetamide]-1-oxobutyl]amino]-3-methylbutyl]. Analytical
Data: .sup.1H NMR (MeOH-d4): 7.14 (2 H, d, J = 8.5); 6.92 (2 H, d,
J = 8.6); 4.63-4.59 (3 H, m); 4.31-4.24 (1 H, m); 2.75 (1 H, t, J =
7.5); 1.72-1.60 (1 H, m); 1.38-1.33 (2 H, m); 1.31 (3 H, s); 1.17
(3 H, d, J = 6.4); 0.95-0.92 (6 H, m). E.3.3 ##STR00583## Chemical
Name: Boronic acid, [(1R)-1-[[(2S,3R)-3-hydroxy-2-
[(tridecanoyl)amino]-1-oxobutyl]amino]-3- methylbutyl]. Analytical
Data: M.p 97-116.degree. C. .sup.1H NMR (MeOH-d4): 4.55 (1 H, d, J
= 3.9); 4.23-4.16 (1 H, m); 2.73 (1 H, t, J = 7.6); 2.36-2.30 (2 H,
m); 1.73-1.60 (3 H, m); 1.40-1.26 (20 H, m); 1.22 (3 H, d, J =
6.4); 0.97-0.90 (9 H, m). E.3.4 ##STR00584## Chemical Name: Boronic
acid, [(1R)-1-[[(2S,3R)-3-hydroxy-2-
[(naphthalene-2-sulfonyl)amino]-1-oxobutyl]amino]-3- methylbutyl].
Analytical Data: .sup.1H NMR (MeOH-d4): 8.44 (1 H, s); 8.04 (2 H,
d, J = 8.6); 7.98 (1 H, d, J = 7.9); 7.87 (1 H, d, J = 8.7);
7.71-7.61 (2 H, m); 4.10-4.02 (2 H, m); 2.36 (1 H, dd, J= 6.5,
8.7); 1.40- 1.26 (1 H, m); 1.12 (3 H, d, J = 5.9); 1.07-0.87 (2 H,
m); 0.74 (3 H, d, J = 6.6); 0.72 (3 H, d, J = 6.6). E.3.5
##STR00585## Chemical Name: Boronic acid,
[(1R)-1-[[(2S,3R)-3-hydroxy-2-[(4-
phenylbenzoyl)amino]-1-oxobutyl]amino]-3- methylbutyl]. Analytical
Data: Mp 200-208.degree. C. .sup.1H NMR (MeOH-d4): 8.00 (2 H, d, J
= 8.4); 7.79 (2 H, d, J = 8.4); 7.70 (2 H, d, J = 7.3); 7.49 (2 H,
t, J = 7.5); 7.41 (1 H, t, J = 7.3); 4.80 (1 H, d, J = 4.1);
4.38-4.31 (1 H, m); 2.78 (1 H, t, J = 7.6); 1.73-1.62 (1 H, m);
1.41-1.35 (2 H, m); 1.31 (3 H, d, J = 6.4); 0.94 (6 H, d, J = 6.5).
E.3.6 ##STR00586## Chemical Name: Boronic acid,
[(1R)-1-[[(2S,3R)-3-hydroxy-2- [(2,2
dimethyl-decanoyl)amino]-1-oxobutyl]amino]-3- methylbutyl].
Analytical Data: .sup.1H NMR (MeOH-d4): 4.40 (1 H, m); 4.05-3.95 (1
H, m) 1.65-1.55 (1 H, m); 1.50-1.40 (2 H, m); 1.25-1.15 (14 H, m);
1.10 (6 H, d, J = 8.8); 1.06 (3 H, d, J = 6.3); 0.82-0.88 (9 H, m).
E.3.7 ##STR00587## Chemical Name: Boronic acid,
[(1R)-1-[[(2S,3R)-3-hydroxy-2-[(4-
Phenoxybenzoyl)amino]-1-oxobutyl]amino]-3- methylbutyl]. Analytical
Data: .sup.1H NMR (DMSO-d6+ MeOH-d4): 7.90 (2 H, d, J = 8.7); 7.38
(2 H, t, J = 7.9); 7.16 (1 H, t, J = 7.4); 7.02 (4 H, t, J = 8.6);
4.53 (1 H, d, J = 4.83); 4.10-3.95 (2 H, m); 2.53- 2.44 (1 H, m);
1.62-1.48 (1 H, m); 1.22-1.49 (2 H, m); 1.09 (3 H, d, J = 6.35);
0.83-0.76 (6 H, m). E.3.8 ##STR00588## Chemical Name: Boronic acid,
[(1R)-1-[[(2S,3R)-3-hydroxy-2-[[4-(1- propoxy
)butylbenzoyl]amino]-1-oxobutyl]amino]-3- methylbutyl]. Analytical
Data: .sup.1H NMR (MeOH-d4): 7.88 (2 H, d, J = 8.9); 7.02 (2 H, d,
J = 8.9); 4.76 (1 H, d, J = 4.0); 4.32 (1 H, dq, J = 4.2, 6.4);
4.03 (2 H, t, J = 6.5); 2.76 (1 H, t, J = 7.6); 1.89-1.79 (2 H, m);
1.72-1.60 (1 H, m); 1.36 (2 H, t, J = 6.9); 1.28 (3 H, d, J = 6.4);
1.08 (3 H, t, J = 7.4); 0.93 (1 H, dd, J = 1.8, 6.6) E.3.9
##STR00589## Chemical Name: Boronic acid,
[(1R)-1-[[(2S,3R)-3-hydroxy-2-[(3-
pyridin-3-yl-benzoyl)amino]-1-oxobutyl]amino]-3- methylbutyl],
hydrochloride salt. Analytical Data: .sup.1H NMR (MeOH-d4): 8.90 (1
H, s); 8.58 (1 H, d, J = 4.26); 8.22 (1 H, t, J = 1.59); 8.21-8.16
(1 H, m); 7.97 (1 H, m); 7.93-7.89 (1 H, m); 7.66 (1 H, t, J =
7.78); 7.60- 7.54 (1 H, m); 4.80 (1 H, d, J = 4.41); 4.38-4.28 (1
H, m); 2.77 (1 H, t, J = 7.63); 1.71-1.60 (1 H, m); 1.39-1.33 (2 H,
m); 1.29 (3 H, d, J = 6.38); 0.95-0.90 (6 H, m). E.3.10
##STR00590## Chemical Name: Boronic acid,
[(1R)-1-[[(2S,3R)-3-hydroxy-2-[(3-
propoxy-benzoyl)amino]-1-oxobutyl]amino]-3- methylbutyl].
Analytical Data: .sup.1H NMR (MeOH-d4): 7.49-7.44 (2 H, m); 7.41 (1
H, t, J = 7.82); 7.18-7.12 (1 H, m); 4.76 (1 H, d, J = 4.21); 4.36-
4.27 (1 H, m); 4.02 (2 H, t, J = 6.45); 2.77 (1 H, t, J = 7.61);
1.90-1.79 (2 H, m); 1.72-1.60 (1 H, m); 1.40-1.34 (2 H, m); 1.29 (3
H, t, J = 6.39); 1.08 (3 H, t, J = 7.42); 0.94 (6 H, d, J = 6.48).
E.3.11 ##STR00591## Chemical Name: Boronic acid,
[(1R)-1-[[(2S,3R)-3-hydioxy-2-[(3-
phenylbenzoyl)amino]-1-oxobutyl]amino]-3- methylbutyl]. Analytical
Data: .sup.1H NMR (MeOH-d4): 8.18 (1 H, t, 1.7); 7.92-7.85 (2 H,
m); 7.73-7.69 (2 H, m); 7.61 (1 H, 7, J = 7.8); 7.52-7.46 (2 H, m);
7.43-7.37 (1 H, m); 4.81 (1 H, d, J = 4.3); 4.38- 4.31 (1 H, m);
2.78 (1 H, t, J = 7.6); 1.72-1.62 (1 H, m); 1.38 (2 H, t, J = 8.7);
1.31 (3 H, d, J = 6.4); 0.94 (6 H, d, J = 6.5). E.3.12 ##STR00592##
Chemical Name: Boronic acid, [(1R)-1-[[(2S,3R)-3-hydroxy-2-[(4-(2-
fluorophenyl)benzoyl)amino]-1-oxobutyl]amino]-3- methylbutyl].
Analytical Data: .sup.1H NMR (MeOH-d4): 8.04-7.99 (2 H, m);
7.75-7.69 (2 H, m); 7.59-7.53 (1 H, m); 7.47-7.40 (1 H, m); 7.34-
7.28 (1 H, m); 7.28-7.20 (1 H, m); 4.81 (1 H, d, J = 4.2);
4.39-4.30 (1 H, m); 2.79 (1 H, 7.63); 1.74-1.62 (1 H, m); 1.42-1.34
(2 H, m); 1.32 (3 H, d, J = 6.39); 0.98-0.92 (6 H, m).
Example E.4
Boronic acid,
[(1R)-1-[[(2S,3R)-3-hydroxy-2-[[4-(3-pyridyl)benzoyl]amino]-1-oxobutyl]am-
ino]-3-methylbutyl]
##STR00593##
[0633] A mixture of 4-(pyridin-3-yl)benzamide,
N-[(1S,2R)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-me-
thano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-hydroxyp-
ropyl]- of Example D.8.3 (155 mg, 0.283 mmol),
2-methylpropylboronic acid (81 mg, 0.793 mmol) and 2N aqueous
hydrochloric acid (0.3 ml) in a heterogeneous mixture of methanol
(3 ml) and hexane (3 ml) was stirred at room temperature for 24
hours. The hexane layer was removed and the methanolic layer was
washed with fresh hexane (about 5 ml). Ethyl acetate (10 ml) was
added to the methanol layer which was then concentrated. The
residue was taken up with ethyl acetate and the mixture was
concentrated. This step was repeated (2-3 times) until an amorphous
white solid was obtained. The solid was then triturated with
diethyl ether (5 ml) and the surnatant was removed by decantation.
This step was repeated. The residue (126 mg) was combined with the
product of a similar preparation (140 mg) and dissolved in ethyl
acetate (about 40 ml) and a small amount of methanol (2-3 ml). The
solution was washed with a mixture of NaCl saturated solution (7
ml) and 10% NaHCO.sub.3 (2 ml). The layers were separated and the
aqueous phase was further washed with ethyl acetate (2.times.20
ml). The combined organic phases were dried over sodium sulfate and
concentrated. The residue was taken up with ethyl acetate (about 20
ml) and the minimum amount of methanol, and then concentrated to
small volume (about 5 ml). The resulting white was collected by
filtration and dried under vacuum at 50.degree. C. (160 mg, 65%
overall yield).
[0634] .sup.1H NMR (MeOH-d4): 8.90 (1H, s); 8.49 (1H, d, J=4.0);
8.20 (1H, d, J=8.1); 8.06 (2H, d, J=8.1); 7.85 (2H, d, J=8.1); 7.58
(1H, t br., J=6.0); 4.80 (1H, d, J=3.9); 4.40-4.29 (1H, m); 2.78
(1H, t, J=7.5); 1.73-1.61 (1H, m); 1.38 (2H, t, J=6.9); 1.31 (3H,
d, J=6.3); 0.94 (6H, d, J=6.31).
[0635] Further compounds prepared according to the above procedure
for Example E.4 are reported in Table E-4.
TABLE-US-00029 TABLE E-4 Ex # Structure Chemical Name and
Analytical Data E.4.1 ##STR00594## Chemical Name: Boronic acid,
[(1R)-1-[[(2S,3R)-3-hydroxy-2- [(2-pyrazinecarbonyl)amino]-1-
oxobutyl]amino]-3-methylbutyl]. Analytical Data: .sup.1H NMR
(MeOH-d4): 9.29 (1H, d, J = 1.3); 8.86 (1H, d, J = 1.3); 8.76-8.74
(1H, m); 4.75 (1H, d, J = 3.2); 4.43-4.36 (1H, m); 2.77 (1H, t, J =
7.6); 1.72-1.60 (1H, m); 1.40-1.36 (2H, m); 1.27 (3H, d, J = 7.6);
0.92 (6H, d, J = 7.6). E.4.2 ##STR00595## Chemical Name: Boronic
acid, [(1R)-1-[[(2S,3R)-3-hydroxy-2-
[(5-butyl-pyridine-2-carbonyl)amino]-1-
oxobutyl]amino]-3-methylbutyl]. Analytical Data: .sup.1H NMR
(MeOH-d4): 8.55 (1H, s); 8.04 (1H, d, J = 7.97); 7.84 (1H, d, J =
7.96); 4.73 (1H, d, J = 2.15); 4.42-4.33 (1H, m); 2.81-2.71 (3H,
m); 1.75-1.6 (3H, m); 1.5-1.3 (5H, m); 1.27 (3H, d, J = 5.64);
1.02-0.95 (3H, m); 0.94-0.89 (6H, m). E.4.3 ##STR00596## Chemical
Name: Boronic acid, [(1R)-1-[[(2S,3R)-3-hydroxy-2-
[(6-phenyl-pyridine-2-carbonyl)amino]-1-
oxobutyl]amino]-3-methylbutyl]. Analytical Data: .sup.1H NMR
(MeOH-d4): 8.20 (2H, d, J = 7.52); 8.18-8.12 (1H, m); 8.11-8.06
(2H, m); 7.60- 7.43 (3H, m); 4.77 (1H, d, J = 2.66); 4.48-4.40 (1H,
m); 2.77 (1H, t, J = 7.54); 1.73-1.60 (1H, m); 1.37 (2H, d, J =
7.3); 1.31 (3H, d, J = 6.36); 0.92 (6H, d, J = 6.55).
Example E.5
Boronic acid,
[(1R)-1-[[(2S)-3-(2-pyrazincarbonylamino)-2-[(4-butylbenzoylamino)]-1-oxo-
propyl]amino]-3-methylbutyl]
##STR00597##
[0637]
2-S-(4-Butylbenzoylamino)-3-(2-pyrazinocarbonylamino)-N-[(1S)-1-[[(-
1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzod-
ioxaborol-2-yl]-3-methylbutyl]amino]carbonyl], from example D.18,
(120 mg, 0.19 mmol, 1 eq.), was dissolved in methanol (2 ml), and
n-hexane (2 ml). The this solution, Isobutylboronic acid (60 mg,
0.57 mmol, 3 eq,) and HCl 4N 1,4-dioxane (0.07 ml, 0.28 mmol, 1.5
eq.) have been added. The resulting bifasic mixture was stirred at
room temperature for 20 h, the n-hexane was removed, the methanolic
solution was washed with n-hexane (2 ml) and evaporated under
reduced pressure. The crude was suspended in diethyl
ether/n-hexane/4 ml), stirred at room temperature and filtered, to
give a white powder. Yield 65%, 69 mg.
[0638] Analytical data: M.p. 145.degree.-150.degree. C.
[0639] .sup.1H NMR (MeOD-d4): 9.3 (1H, s); 8.85 (1H, s); 8.75 (1H,
s); 7.8 (2H, d); 7.3 (2H, d); 5.1 (2H, t); 4 (2H, dd); 2.8 (1H, t);
2.75 (2H, t); 1.65 (3H, m); 1.4 (4H, m); 1.0 (3H, t) 0.9 (6H,
dd).
[0640] Further compounds prepared according to the above procedure
for Example E.5 are reported in Table E-5.
TABLE-US-00030 TABLE E-5 Ex # Structure Chemical Name and
Analytical Data E.5.1 ##STR00598## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-3-(acetylamino)-2-
[(decanoylamino)]-1-oxopropyl]amino]-3- methylbutyl] Analytical
Data: .sup.1H NMR (MeOD-d4): 4.70 (1H, d); 3.50 (2H, m); 2.75 (1H,
t); 2.25 (2H, t); 2.8 (1H, t); 1.95 (3H, s); 1.65 (3H, m); 1.35
(14H, m); 0.9 (9H, m) E.5.2 ##STR00599## Chemical Name: Boronic
acid, [(1R)-1-[[(2S)-3-(propylureido)-2-
[(4-butyl)-benzoylamino]-1-oxopropyl]amino]-3- methylbutyl]
Analytical Data: .sup.1H NMR (MeOD-d4): 7.80 (2H, d); 7.28 (7H, m);
4.45 (1H, br); 3.7 (1H, br); 3.1 (2H, t); 2.65 (2H, t); 1.7-1.2
(10H, m); 0.9 (12H, m) E.5.3 ##STR00600## Chemical Name: Boronic
acid, [(1R)-1-[[(2S)-3-
(methanesulfamido)-2-[(4-butyl)-benzoylamino]-
1-oxopropyl]amino]-3-methylbutyl] Analitical Data: .sup.1H NMR
(MeOD-d4): 7.80 (2H, d); 7.28 (7H, m); 3.65 (2H, m); 3.0 (3H, s);
2.8 (1H, br); 1.65 (3H, m); 1.35 (4H, m); 0.9 (12H, m). M.p.
120.degree.-123.degree. C. E.5.4 ##STR00601## Chemical Name:
Boronic acid, [(1R)-1-[[(2S)-3-[2-(1H-
pyrazol)ethyl]-2-[(4-butyl)-benzoylamino]-1-
oxopropyl]amino]-3-methylbutyl] Analytical Data: .sup.1H NMR
(MeOD-d4): 7.68 (2H, d); 7.65 (1H, d); 7.43 (1H, d); 7.27 (1H, m);
7.24 (2H, d); 5.06 (1H, t); 4.54 (2H, m); 2.60 (2H, m); 1.5 (3H,
m), 1.60-1.3 (4H, m); 0.86 (3H, t); 0.80 (6H, d). E.5.5
##STR00602## Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-
(methanesulfamido)-2-[(4-butyl)-benzoylamino]-
1-oxopropyl]amino]-3-methylbutyl] Analytical Data: .sup.1H NMR
(MeOD-d4): 7.85 (2H, d); 7.75 (2H, d); 7.35-7.25 (4H, dd); 4.85
(1H, t); 3.9 (2H, dd); 2.8 (1H, t); 2.75 (2H, t); 2.4 (3H, s), 1.65
(3H, m); 1.35 (5H, m); 1.05-0.80 (9H, m). E.5.6 ##STR00603##
Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-
[(carbobenzyloxyamino]-2-[(4-
butylbenzoylamino)]-1-oxopropyl]amino]-3- methylbutyl] Analytical
Data: .sup.1H NMR (MeOD-d4): 7.80 (2H, d); 7.28 (7H, m); 5.2 (2H,
dd); 3.6 (2H, d); 2.8 (1H, t); 2.75 (2H, t); 1.65 (3H, m); 1.3 (4H,
m); 1.0 (9H, m). M.p. 92.degree.- 96.degree. C. E.5.7 ##STR00604##
Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-[(thien-2-
ylcarbonyl)amino]-2-[(4-butylbenzoylamino)]-1-
oxopropyl]amino]-3-methylbutyl] Analytical Data: .sup.1H NMR
(MeOD-d4): 7.80 (2H, d); 7.7 (2H, m); 7.3 (2H, d); 7.2 (1H, t); 4.9
(2H, dd); 3.9 (2H, dd); 2.8 (1H, t); 2.75 (2H, t); 1.65 (3H, m);
1.3 (4H, m); 1.0 (3H, t) 0.9 (6H, dd). E.5.8 ##STR00605## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-3-(acetylamino)-2-
[4-butyl-benzoylamino)]-1-oxopropyl]amino]-3- methylbutyl]
Analytical Data: .sup.1H NMR (MeOD-d4): 7.8 (2H, d); 7.3 (2H, d);
4.8 (1H, m); 3.7 (2H, dd); 2.8 (1H, t); 2.75 (2H, t); 2 (3H, s);
1.65 (3H, m); 1.4 (4H, m); 1.0-0.9 (3H, t), (6H, dd). M.p.
107.degree.-109.degree. C. E.5.9 ##STR00606## Chemical Name:
Boronic acid, [(1R)-1-[[(2S)-3-[(thien-2-
ylcarbonyl)amino)]-2-[(decanoylamino)]-1-
oxopropyl]amino]-3-methylbutyl] Analytical Data: .sup.1H NMR
(MeOD-d4): t 7.7 (2H, d); 7.15 (1H, t); 4.8 (1H, m); 3.7 (2H, dd);
2.8 (1H, t); 2.75 (2H, t); 2.25 (2H, t); 1.65 (3H, m); 1.4 (14H,
m); 1.0-0.9 (3H, t). E.5.10 ##STR00607## Chemical Name: Boronic
acid, [(1R)-1-[[(2S)-3-(hexanoylamino)-
2-[(4-butylbenzoylamino)]-1-oxopropyl]amino]- 3-methylbutyl]
Analytical Data: .sup.1H NMR (MeOD-d4): 7.8 (2H, d); 7.3 (2H, d);
3.7 (2H, dd); 2.8 (1H, t); 2.75 (2H, t); 2.2 (2H, t); 1.65 (5H, m);
1.4 (9H, m); 1.0-0.9 (12H, t). E.5.11 ##STR00608## Chemical Name:
Boronic acid, [(1R)-1-[[(2S)-3-[4-fluoro-
benzenesulfonamide]-2-[(4-butylbenzoyl)amino]-
1-oxopropyl]amino]-3-methylbutyl] Analytical Data: .sup.1H NMR
(MeOD-d4): 7.95 (2H, dd); 7.8 (2H, d); 7.3 (4H, m); 4.8 (1H, m);
3.4 (2H, m); 2.85 (1H, t); 2.7 (2H, t); 1.7 (3H, m); 1.4 (4H, m);
1.0-0.9 (9H, t). M.p. 130.degree.-132.degree. C. E.5.12
##STR00609## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-3-[4-fluoro-
benzenesulfonamide]-2-[(decanoyl)amino]-1-
oxopropyl]amino]-3-methylbutyl] Analytical Data: .sup.1H NMR
(MeOD-d4): 7.95 (2H, dd); 7.35 (2H, t); 4.45 (1H, t); 3.0 (2H, m);
3.4 (2H, m); 2.1 (2H, t); 1.65-1.35 (3H, m); 1.25 (14H, m); 0.85
(9H, m). E.5.13 ##STR00610## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-3-(hexanonylamino)-
2-[(decanoylamino)]-1-oxopropyl]amino]-3- methylbutyl] Analytical
Data: .sup.1H NMR (MeOD-d4): 4.45 (1H, t); 3.3 (2H, m); 2.1 (4H,
tt); 1.65-1.35 (3H, m); 1.25 (18H, m); 0.85 (12H, m). E.5.14
##STR00611## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-3-(hexanonylamino)-
2-[(cyclopropancarbonylamino)]-1- oxopropyl]amino]-3-methylbutyl]
3-methylbutyl]amino]carbonyl]-2- (cyclopropancarbonylamino)ethyl]-
Analytical Data: .sup.1H NMR (MeOD-d4): 7.8 (2H, d); 7.2 (2H, d);
4.6 (1H, br); 3.4 (2H, m); 3.0 (2H, s); 2.7 (2H, m); 1.5 (4H, m);
1.3 (3H, m); 1.2 (4H, m); 0.9-0.6 (15H, m). E.5.15 ##STR00612##
Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-[(3,4-
dimethoxyphenyl)acetylamino]-2-[(4-
butylbenzoylamino)]-1-oxopropyl]amino]-3- methylbutyl] Analytical
Data: M.p. 150.degree.-152.degree. C. .sup.1H NMR (MeOD-d4): 7.7
(2H, d); 7.2 (2H, d); 6.8 (1H, s); 6.75 (2H, m); 4.7 (1H, m); 3.7
(6H, m); 3.54 (2H, s); 3.35 (2H, s); 2.66 (3H, t); 1.6 (2H, t);
1.4-1.2 (2H, m); (2H, m); (2H, m); 0.9 (3H, t), 0.8 (6H, d). E.5.16
##STR00613## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-3-[1-N-methyl-2- pyrrolylcarbonylamino]-2-[(4-
butylbenzoyl)amino]-1-oxopropyl]amino]-3- methylbutyl] Analytical
Data: .sup.1H NMR (MeOD-d4): 7.8 (2H, d); 7.3 (2H, d); 6.9 (1H, d);
6.7 (1H, d); 6 (1H, t); 4.8 (1H, t); 3.9 (3H, s); 3.7 (2H, m); 2.7
(3H, m); 1.65 (3H, m); 1.35 (4H, m); 0.9-0.6 (9H, m). M.p.
130.degree.-135.degree. C. E.5.17 ##STR00614## Chemical Name:
Boronic acid, [(1R)-1-[[(2S)-3-[4- sulfamylbenzoylamino]-2-[(4-
butylbenzoyl)amino]-1-oxopropyl]amino]-3- methylbutyl] Analytical
Data: .sup.1H NMR (MeOD-d4): 7.95 (4H, dd); 7.8 (2H, d); 7.3 (2H,
d); 4.9 (1H, t); 3.7 (2H, d); 2.7 (2H, t); 2.6 (1H, t); 1.6 (3H,
m); 1.2 (4H, m); 0.95-0.8 (9H, m). M.p. 156.degree.-159.degree. C.
E.5.18 ##STR00615## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-3-(nicotinoylamino)-
2-[(4-butylbenzoylamino)]-1-oxopropyl]amino]- 3-methylbutyl]
Analytical Data: .sup.1H NMR (MeOD-d4): 9.1 (1H, s); 8.8 (1H, d);
8.4 (1H, d); 7.8 (2H, d); 7.7 (1H, t); 7.3 (2H, d); 4.9 (1H, t);
3.7 (2H, m); 2.7 (2H, t); 2.6 (1H, t); 1.6 (3H, m); 1.4-1.2 (7H,
m); 0.95-0.8 (9H, m). E.5.19 ##STR00616## Chemical Name: Boronic
acid, [(1R)-1-[[(2S)-3-(3-phenylureido)-
2-(4-butylbenzoylamino)-1-oxopropyl]amino]-3- methylbutyl]
Analytical Data: .sup.1H NMR (MeOD-d4): 8.8 (1H, d); 7.35 (2H, d);
7.25 (2H, d); 7.2 (2H, t); 6.9 (1H, t); 4.7 (1H, t); 3.7-3.4 (2H,
m); 2.7 (2H, t); 2.6 (1H, t); 1.6 (3H, m); 1.4-1.2 (4H, m);
0.95-0.8 (9H, m). E.5.20 ##STR00617## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-3-[(4- methylsulfonyl)benzoylamino]-2-[(4-
butylbenzoylamino)]-1-oxopropyl]amino]-3- methylbutyl] Analytical
Data: .sup.1H NMR (MeOD-d4): 8.0 (4H, m); 7.8 (2H, d); 7.25 (2H,
d); 4.9 (1H, br); 3.75 (2H, m); 3.2 (3H, s); 2.7 (2H, t); 2.6 (1H,
t); 1.6 (3H, m); 1.4-1.2 (4H, m); 0.95-0.8 (9H, m). M.p.
168.degree.-170.degree. C. E.5.21 ##STR00618## Chemical Name:
Boronic acid, [(1R)-1-[[(2S)-3-(3-phenylureido)-
2-(decanoylamino)-1-oxopropyl]amino]-3- methylbutyl] Analytical
Data: .sup.1H NMR (MeOD-d4): 7.35 (2H, d); 7.28 (2H, dd); 7.0 (2H,
t); 3.6 (2H, d); 2.75 (1H, t); 2.2 (2H, t); 1.65 (3H, m); 1.3 (14H,
m); 0.9 (9H, m) E.5.22 ##STR00619## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-3-(nicotinoylamino)-
2-(decanoylamino)-1-oxopropyl]amino]-3- methylbutyl] Analytical
Data: .sup.1H NMR (MeOD-d4): 9.0 (1H, s); 8.8 (1H, d); 8.3 (1H, d);
7.5 (1H, t); 4.9 (1H, m); 3.9-3.6 (2H, m); 2.75 (1H, t); 2.2 (2H,
t); 1.65 (3H, m); 1.3 (14H, m); 1.0-0.9 (9H, m). M.p.
136.degree.-141.degree. C. E.5.23 ##STR00620## Chemical Name:
Boronic acid, [(1R)-1-[[(2R)-3-(4-
methylphenylcarbonyl)-2-(decanoylamino)-1-
oxopropyl]amino]-3-methylbutyl] Analytical Data: .sup.1H NMR
(MeOD-d4): 8.85 (2H, d); 8.0 (2H, d); 7.3 (4H, m); 5.0 (1H, m); 3.9
(2H, m); 2.75 (3H, m); 1.65 (3H, m); 1.3 (9H, m); 0.9 (9H, m)
E.5.24 ##STR00621## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-3-[4-(1H-tetrazolyl)- phenylcarbonylamino]-2-[(4-
butylbenzoylamino)]-1-oxopropyl]amino]- 3-methylbutyl] Analytical
Data: .sup.1H NMR (MeOD-d4): 8.15 (2H, d); 7.9 (2H, d); 7.8 (2H,
d); 7.3 (2H, d); 5.0 (1H, t); 3.9 (2H, m); 2.8 (1H, t); 2.7 (2H,
t); 1.65 (3H, m); 1.3 (4H, m); 0.9 (9H, m). M.p. >250.degree. C.
E.5.25 ##STR00622## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-3-(2- isoxazolylcarbonylamino)-2-[(4-
butylbenzoylamino)]-1-oxopropyl]amino]-3- methylbutyl] Analytical
Data: .sup.1H NMR (MeOD-d4): 8.4 (1H, s); 7.7 (2H, d); 7.2 (2H, d);
6.9 (1H, s); 4.9 (1H, t); 3.8 (2H, m); 2.7 (1H, t); 2.6 (2H, t);
1.5 (3H, m); 1.25 (4H, m); 0.8 (9H, m) M.p. 175.degree.-180.degree.
C. E.5.26 ##STR00623## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-3-[1-methyl-1H- imidazole-4-sulfamoyl]-2-[(4-
butylbenzoyl)amino]-1-oxopropyl]amino]-3- methylbutyl] Analytical
Data: .sup.1H NMR (MeOD-d4): 8.8 (2H, d); 8.7 (2H, s); 7.3 (2H, d);
4.9 (1H, br); 3.8 (3H, s); 3.5 (2H, m); 2.8 (1H, t); 2.7 (2H, t);
1.65 (3H, m); 1.35 (4H, m); 0.9 (9H, m), M.p.
120.degree.-123.degree. C. E.5.27 ##STR00624## Chemical Name:
Boronic acid, [(1R)-1-[[(2S)-3-[6-morpholin-4-yl-
pyridine-3-sulfamoyl]-2-[(4-butylbenzoyl)amino]-
1-oxopropyl]amino]- 3-methylbutyl] hydrochloride Analytical Data:
.sup.1H NMR (MeOD-d4): 8.35 (1H, s); 8.1 (1H, d); 7.8 (2H, d); 7.3
(3H, m); 4.9 (1H, br); 3.9 (4H, t); 3.8 (4H, t); 3.5 (2H, m); 2.8
(1H, t); 2.7 (2H, t); 1.65 (3H, m); 1.35 (4H, m); 0.9 (9H, m). M.p.
182.degree.-184.degree. C. E.5.28 ##STR00625## Chemical Name:
Boronic acid, [(1R)-1-[[(2S)-3-(6- morpholinonicotinamide]-2-[(4-
butylbenzoyl)amino]-1-oxopropyl]amino]- 3-methylbutyl] Analytical
Data: .sup.1H NMR (MeOD-d4): 8.5 (1H, s); 7.9 (1H, d); 7.7 (2H, d);
7.2 (2H, d); 6.7 (1H, d); 4.9 (1H, t); 3.8 (2H, ts); 3.7 (4H, d);
3.4 (4H, d); 2.65 (1H, t); 2.6 (2H, t); 1.60 (3H, m); 1.25 (4H, m);
0.9 (9H, m). M.p. 178.degree.-180.degree. C. E.5.29 ##STR00626##
Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-(4-(1,3-dimethyl-
1H-pyrazole-5-carbonylamino]-2-[(4-
butylbenzoyl)amino]-1-oxopropyl]amino]- 3-methylbutyl]
hydrochloride Analytical Data: .sup.1H NMR (MeOD-d4): 7.8 (1H, d);
7.3 (2H, d); 6.65 (1H, s); 5.0 (1H, t); 3.9 (2H, m); 2.8 (1H, t);
2.7 (2H, t); 2.3 (3H, s); 1.60 (3H, m); 1.35 (4H, m); 0.9 (9H, m).
E.5.30 ##STR00627## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-3-[4-fluoro- benzenesulfonamide]-2-[(4-
phenoxybenzoyl)amino]-1-oxopropyl]amino]-3- methylbutyl] Analytical
Data: .sup.1H NMR (MeOD-d4): 7.95 (2H, m); 7.9 (2H, d); 7.4 (2H,
m); 7.3 (2H, t); 7.25 (1H, t); 7.1 (2H, d); 7.0 (2H, d); 3.4 (2H,
m); 2.8 (1H, br); 1.7 (1H, m); 1.40 (2H, m); 0.9 (6H, d). M.p.
150.degree.-155.degree. C. E.5.31 ##STR00628## Chemical Name:
Boronic acid, [(1R)-1-[[(2S)-3-(4-(1,3-dimethyl-
1H-pyrazole-5-carbonylamino]-2-[(4-
phenoxybenzoyl)amino]-1-oxopropyl]amino]-
3-methylbutyl]carbonylamino]ethyl]- Analytical Data: .sup.1H NMR
(MeOD-d4): 7.9 (2H, d); 7.45 (2H, t); 7.25 (1H, t); 7.11 (2H, d);
7.05 (2H, d); 6.55 (1H, s); 5.0 (1H, t); 4.1 (3H, s); 3.9 (2H, m);
2.8 (1H, t); 2.25 (3H, s); 1.6 (1H, m); 1.35 (2H, m); 0.9 (6H, d).
M.p. 145.degree.-148.degree. C. E.5.32 ##STR00629## Chemical Name:
Boronic acid, [(1R)-1-[[(2S)-3-(4-phenylureido]-
2-[(4-phenoxybenzoyl)amino]-1- oxopropyl]amino]- 3-methylbutyl]
Analytical Data: .sup.1H NMR (MeOD-d4): 7.9 (2H, d); 7.40 (2H, t);
7.35 (2H, d); 7.25 (3H, m); 7.10 (2H, d); 7.05 (3H, d); 3.75 (2H,
m); 2.8 (1H, t); 1.75 (1H, m); 1.4 (2H, m); 0.9 (6H, d). M.p.
155.degree.-158.degree. C. E.5.33 ##STR00630## Chemical Name:
Boronic acid, [(1R)-1-[[(2S)-3-(4-
phenybenzamide]-2-[(4-butylbenzoyl)amino]-1- oxopropyl]amino]-
3-methylbutyl] Analytical Data: .sup.1H NMR (MeOD-d4): 7.9 (2H, d);
7.8 (2H, d); 7.75 (2H, d); 7.70 (2H, d); 7.45 (2H, t); 7.35 (1H,
d); 7.30 (1H, d); 5.0 (1H, t); 3.95 (2H, m); 2.8 (1H, t); 2.7 (2H,
t); 1.65 (3H, m); 1.4 (2H, m); 1.0 (3H, t) 0.9 (6H, d). M.p.
178.degree.-180.degree. C. E.5.34 ##STR00631## Chemical Name:
Boronic acid, [(1R)-1-[[(2S)-3-(4-
phenylbenzamide]-2-[(4-phenoxybenzoyl)amino]- 1-oxopropyl]amino]-
3-methylbutyl] Analytical Data: .sup.1H NMR (MeOD-d4): 7.9 (4H, m);
7.80 (2H, d); 7.70 (2H, d); 7.4 (4H, m); 7.20 (1H, t); 7.05 (4H,
d); 5.0 (1H, t); 3.9 (2H, m); 2.8 (1H, t); 1.6 (1H, m); 1.4 (2H,
m); 0.9 (6H, d). M.p. 158.degree.-160.degree. C. E.5.35
##STR00632## Chemical Name: Boronic acid, [(1R)-1-[[(2S)-3-
(phenylpropionamide]-2-[(4- butylbenzoyl)amino]-oxopropyl]amino]-
3-methylbutyl] Analytical Data: .sup.1H NMR (MeOD-d4): 7.85 (2H,
m); 7.4 (2H, d); 7.5 (1H, d); 7.45 (2H, m); 7.35 (2H, d); 5.0 (1H,
t); 3.95 (2H, m); 2.8 (1H, t); 2.7 (2H, t); 1.7 (3H, m); 1.4 (4H,
m); 1.0 (3H, t) 0.9 (9H, m). M.p. 138.degree.-140.degree. C.
E.5.36 ##STR00633## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-3-(4- methylphenylsulfonyl)-ureido]-2-[(4-
butylbenzoyl)amino]-1-oxopropyl]amino]- 3-methylbutyl] Analytical
Data: .sup.1H NMR (MeOD-d4): 7.85 (2H, d); 7.75 (2H, d); 7.3 (2H,
d); 7.25 (2H, d); 4.7 (1H, t); 3.65 (2H, m); 2.75 (1H, t); 2.7 (2H,
t); 1.7 (3H, m); 1.4 (4H, m); 1.0-0.9 (9H, m). M.p.
175.degree.-177.degree. C. E.5.37 ##STR00634## Chemical Name:
Boronic acid, [(1R)-1-[[(2S)-3-(4-(2-(4-pyridyl)-
1,3-thiazole-4-carbonylamino)]-2-[(4-
butylbenzoyl)amino]-1-oxopropyl]amino]- 3-methylbutyl] Analytical
Data: .sup.1H NMR (MeOD-d4): 8.7 (2H, d); 8.45 (1H, s); 8.05 (2H,
d) 7.8 (2H, d); 7.3 (2H, d); 5.05 (1H, t); 4.0 (2H, m); 2.8 (1H,
t); 2.7 (2H, t); 1.7 (3H, m); 1.4 (4H, m); 0.9 (3H, t); 0.8 (6H,
dd). M.p. 155.degree.- 158.degree. C. E.5.38 ##STR00635## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-3-(1-
methanesulfonylpiperidine-4-carbonylamino)-2-
[(4-butylbenzoylamino)]-1- oxopropyl]amino]-3-methylbutyl]
Analytical Data: .sup.1H NMR (MeOD-d4): 9.9 (1H, br); 8.35 (1H, t);
7.8 (2H, d); 7.3 (2H, d); 4.9 (1H, t); 3.7 (4H, m); 2.8 (3H, s);
2.75 (4H, m); 2.3 (1H, m); 1.85-1.6 (7H, m); 1.3 (4H, m) 0.9 (9H,
m); M.p. 170.degree.- 173.degree. C. E.5.39 ##STR00636## Chemical
Name: Boronic acid, [(1R)-1-[[(2S)-3-[(2-
thiophene)sulfonylamino]-2-[(4-
butylbenzoylamino)]-1-oxopropyl]amino]-3- methylbutyl] Analytical
Data: .sup.1H NMR (MeOD-d4): 7.95 (1H, dd); 7.8 (2H, d); 7.58 (1H,
dd); 7.32 (2H, d); 7.18 (1H, dd); 4.8 (1H, m); 3.23 (2H, m); 2.66
(1H, t); 1.3-1.23 (8H, m); 0.9 (3H, t), 0.8 (6H, d). E.5.40
##STR00637## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-3-(4-(1H-1,2,4- triazol-1-yl)benzoylamide)]-2-[(4-
butylbenzoyl)amino]-1H-oxopropyl]amino]- 3-methylbutyl]
hydrochloride Analytical Data: .sup.1H NMR (MeOD-d4): 9.8 (1H, s);
8.6 (1H, s); 8.08 (2H, d); 8.01 (2H, d); 7.8 (2H, d); 7.3 (2H, d);
5.05 (1H, t); 3.9 (2H, m); 2.8 (1H, t); 2.7 (2H, t); 1.6 (3H, m);
1.3 (4H, m); 1.0 (3H, t); 0.9 (6H, dd). Mp. 192.degree.-195.degree.
C. E.5.41 ##STR00638## Chemical Name: Boronic acid,
[(1R)-1-[[(2R)-3-(4- methylphenylcarbonyl)-2-(decanoylamino)-1-
oxopropyl]amino]-3-methylbutyl] Analytical Data: .sup.1H NMR
(MeOD-d4): 7.85 (2H, d); 7.8 (2H, d); 7.35 (4H, m); 5 (1H, m); 4.05
(1H, m); 3.95 (1H, m); 2.75 (2H, t); 1.65 (2H, m); 1.35 (10H, m);
1.0 (3H, t). 0.85 (6H, d). E.5.42 ##STR00639## Chemical Name:
Boronic acid, [(1R)-1-[[(2S)-3-(4-phenylureido]-
2-(decanoylamino)-1-oxopropyl]amino]- 3-methylbutyl] E.5.43
##STR00640## Chemical Name: Boronic acid,
[(1R)-1-[[(2S)-3-acetylamino-2- decanoylamino-1-oxopropyl]amino]-
3-methylbutyl]
Example F.1
Decanamide,
N-[(1S)-1-[[[(1R)-1-[(4R,5R)-4,5-dicyclohexyl-[1,3,2]dioxaborolan-2-yl]-3-
-methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]amino]butyl]-
##STR00641##
[0642] To a suspension of boronic acid,
[(1R)-1-[[(2S)-5-[[imino(nitroamino)methyl]amino]-2-[(decanoyl)amino]-1-o-
xopentyl]amino]-3-methylbutyl]-, (125 mg, 0.26 mmol) obtained as in
Example E.2, in a mixture of diethyl ether (0.5 ml) and
dichloromethane (1 ml), a few drops of methanol were added until
complete dissolution of the solid.
(1R,2R)-1,2-dicyclohexyl-1,2-ethanediol (61 mg, 0.26 mmol) was
added and the mixture was stirred at room temperature for 5 hours.
The reaction mixture was concentrated to dryness and the residue
was purified by column chromatography (silica gel) eluting with a
50:50 ethyl acetater:hexane mixture. The product was then
triturated with hexane and the solvent was removed by decantation.
The trituration was repeated two further times. The product was
obtained as a waxy solid (65 mg, 37% yield).
[0643] M.p. 75-100.degree. C.
[0644] .sup.1H NMR (DMSO-d.sub.6): 8.99 (1H, d, J=2.5 Hz); 8.52
(1H, br); 7.98 (1H, d, J=8.05); 7.88 (2H, br); 3.48 (2H, d, J=5.7);
3.14 (2H, m); 2.55 (1H, m); 2.19 (1H, m); 2.10 (2H, m); 1.79 (2H,
m); 1.74-1.35 (16H, m); 1.24 (22H, m); 1.12 (5H, m); 0.89 (4H, m);
0.84 (9H, m).
Example F.2
4-Phenylbutanamide,
N-[(1S)-1-[[[(1R)-1-[13,15-dioxa-[4-bora-dispiro[5.0.5.3]-pentadec-14-yl]-
-3-methylbutyl]amino]carbonyl]-4-[[imino(nitroamino)methyl]-amino]butyl]-
##STR00642##
[0646] The title compound was prepared according to the above
procedure for Example F.1 using the appropriate boronic acid
starting material and bicyclohexyl-1,1'-diol.
[0647] Analytical results: .sup.1H NMR (DMSO-d.sub.6): 8.79 (1H, d,
J=2.5 Hz); 8.52 (1H, br); 8.00 (1H, d, J=7.94); 7.85 (2H, br);
7.31-7.23 (2H, m); 7.20-7.14 (3H, m); 4.40-4.30 (1H, m); 3.15 (2H,
m); 2.55 (3H, m); 2.14 (2H, t, J=7.3 Hz); 1.78 (2H, q, J=7.3 Hz);
1.70-0.97 (27H, m); 0.84 (3H, t, J=6.7 Hz); 0.83 (3H, t, J=6.7
Hz).
Example F.2.1
4-Butylbenzamide,
N-[(1S,2R)-1-[[[(1R)-1-[13,15-dioxa-14-bora-dispiro[5.0.5.3]pentadec-14-y-
l]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]-
##STR00643##
[0649] The title compound was prepared according to the above
procedure for Example F.1 using the appropriate boronic acid
starting material and bicyclohexyl-1,1'-diol.
[0650] Analytical results: .sup.1H NMR (DMSO-d.sub.6): 8.98 (1H, s
br.); 8.00 (1H, d, J=8.5); 7.81 (2H, d, J=8.2); 7.31 (2H, d,
J=8.2); 5.03 (1H, d, J=6.2); 4.49 (1H, dd, J=8.5, 5.0); 4.07-3.98
(1H, m); 2.64 (1H, t, J=7.6); 2.57-2.50 (1H, m); 1.65-1.21 (21H,
m); 1.14-1.00 (9H, m); 0.90 (3H, t, J=7.4); 0.85 (6H, d, 6.5).
Example G.1
10-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-decanoic acid
##STR00644##
[0651] Step 1: 2-undec-10-enyl-1,3-dioxo-1,3-dihydroisoindole
[0652] To a mixture of 10-undecen-1-ol (4.23 g, 24.8 mmol),
phthalimide (3.65 g, 24.8 mmol) and triphenylphosphine (6.51 g,
24.8 mmol) in anhydrous tetrahydrofuran (30 ml), a solution of DEAD
(3.9 ml, 24.8 mmol) in anhydrous tetrahydrofuran (10 ml) was slowly
added while keeping the temperature below 8-10.degree. C. After 2
hours further DEAD (1.0 ml, 6.37 mmol) and triphenylphosphine (1.3
g, 4.96 mmol) were added and the mixture was stirred at room
temperature overnight. The reaction mixture was concentrated and
the residue was triturated with diethyl ether (50 ml). The solid
was removed by filtration and washed with diethyl ether (2.times.50
ml). The combined filtrates were concentrated and the residue was
triturated with hexane (50 ml) at 40.degree. C. The resulting solid
was removed by filtration and washed with hexane (2.times.50 ml).
The combined filtrates were concentrated and the residue was
purified by column chromatography eluting with 10:2 hexane:ethyl
acetate mixture. The product was obtained as a low-melting white
solid (4.9 g, 66% yield). M.p. 25-30.degree. C.
[0653] .sup.1H NMR (DMSO-d.sub.6) 7.83 (4H, m); 5.76 (1H, m); 4.96
(1H, dq, J=17.2, 1.6 Hz); 4.90 (1H, ddt, J=10.2, 2.2, 1.1); 3.54
(2H, t, J=7.1), 1.97 (2H, q, J=6.7); 1.56 (2H, m); 1.35-1.15 (14H,
m).
Step 2: 10-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)decanoic acid
[0654] A solution of 2-undec-10-enyl-1,3-dioxo-1,3-dihydroisoindole
(2 g, 6.68 mmol) of Step 1 and Aliquat.RTM. 336 (0.2 g) in a
mixture of hexane (20 ml) and acetic acid (6 ml) was added dropwise
to a solution of potassium permanganate (2.76 g, 20 mmol) in water
(28 ml) while cooling at 0.degree. C. The reaction mixture was
stirred at room temperature for 7 hours, then an aqueous solution
of sodium bisulfite was added until disappearance of the purple
colour. The mixture was then extracted with ethyl acetate and the
organic phase was dried over sodium sulfate and concentrated. The
residue was purified by silica gel column chromatography eluting
with 2:1 hexane:ethyl acetate mixture. The product was obtained as
a white solid (1.29 g, 61% yield). M.p. 58-60.degree. C.
[0655] .sup.1H NMR (DMSO-d.sub.6) 11.95 (1H, br); 7.85 (4H, m);
3.55 (2H, t, J=7.2 Hz); 2.17 (2H, t, J=7.2 Hz); 1.7-1.4 (4H, m);
1.22 (10H, m).
Example G.2
6-(Benzenesulfonylamino)hexanoic acid
[0656] Benzenesulfonyl chloride (2.5 ml, 19 mmol) was added to a
solution of 6-aminohexanoic acid (1 g, 7.62 mmol) in 2N NaOH (22
ml) and dioxane (3 ml), while stirring at 0.degree. C.-5.degree. C.
The mixture was allowed to warm to room temperature and stirred for
1 hour. The reaction mixture was washed with ethyl acetate (50 ml),
then acidified to pH 2 with 37% hydrochloric acid and extracted
with ethyl acetate (2.times.50 ml). The combined organic layers
were dried over sodium sulfate and concentrated. The residue was
triturated with hexane. The solid was collected by filtration and
dried under vacuum at 50.degree. C. affording 1.1 g of the title
compound (55% yield). M.p. 113-115.degree. C.
[0657] .sup.1H NMR (DMSO-d.sub.6): 11.96 (1H, s); 7.79 (2H, m);
7.60 (4H, m); 2.71 (2H, m); 2.13 (2H, t, J=7.14 Hz); 1.38 (4H, m);
1.21 (2H, m).
Example G.3
6-(Ethylsulfonylamino)hexanoic acid
[0658] A solution of ethanesulfonyl chloride (3.9 ml, 41.1 mmol) in
dioxane (10 ml) was added to a solution of 6-aminohexanoic acid (2
g, 15.2 mmol) in 1N NaOH (56 ml) and dioxane (10 ml), while
stirring at 0.degree. C.-5.degree. C. The pH of the reaction
mixture was adjusted to 8-9 by addition of 25% sodium hydroxide
solution. The mixture was allowed to warm to room temperature and
stirred for 30 minutes. Further 25% NaOH solution was added to
adjust the pH to about 11. After 3.5 h 1N hydrochloric acid (15 ml)
and ethyl acetate (60 ml) were added. The organic layer was dried
over sodium sulfate and concentrated. The residue was triturated
with a mixture of diethyl ether (5 ml) and hexane (15 ml). The
solid was collected by filtration and dried affording 1.3 g of the
title compound (40% yield).
[0659] .sup.1H NMR (DMSO-d.sub.6): 11.9 (1H, s); 6.97 (1H, t, J=5.7
Hz); 2.97 (2H, q, J=7.1); 2.88 (2H, q, J=6.6); 2.2 (2H, t, J=7.3);
1.47 (4H, m); 1.29 (2H, m); 1.18 (3H, t, J=7.3).
Example G.4
8-(Ethylsulfonylamino)octanoic acid
[0660] A solution of ethanesulfonyl chloride (1.5 ml, 15.7 mmol) in
dioxane (5 ml) was added to a solution of 8-aminooctanoic acid (1
g, 6.28 mmol) in 1N NaOH (22 ml) and dioxane (5 ml), while stirring
at 0.degree. C.-5.degree. C. The mixture was allowed to warm to
room temperature and stirred for 3.5 minutes. During this period,
at 1 hour intervals, the pH was adjusted to 7-8 by addition of 25%
NaOH solution. The reaction mixture was washed with diethyl ether
(30 ml). The pH was adjusted to 1-2 by addition of 1N HCl and the
mixture was extracted with ethyl acetate (70 ml). The organic layer
was dried over sodium sulfate and concentrated. The residue was
triturated with a mixture of diethyl ether. The solid was collected
by filtration and dried under vacuum affording 600 mg of the title
compound (38% yield).
[0661] .sup.1H NMR (DMSO-d.sub.6): 11.9 (1H, s); 6.96 (1H, t, J=6
Hz); 2.96 (2H, q, J=7.1); 2.88 (2H, q, J=6.6); 2.2 (2H, t, J=7.3);
1.45 (4H, m); 1.26 (6H, m); 1.18 (3H, t, J=7.3).
Example G.5
3-Amino-2-S-[(1,1-dimethylethoxycarbonyl)amino]-propionic acid,
benzyl ester
##STR00645##
[0662] Step 1: N-tert-butoxycarbonyl-L-asparagine [Commercially
available]
##STR00646##
[0664] L-asparagine (15 g, 0.113 mol, 1 eq.) and sodium carbonate
(12 g, 0.113 mol) were dissolved in water (225 ml) and 1,4-dioxane
(225 ml) at r.t. To this solution, di-tert-butyl-dicarbonate (30 g,
0.137 mol, 1.2 eq.) was added and the mixture was stirred
overnight. The solvent was evaporated under reduced pressure till
1,4-dioxane was distilled and the pH adjusted to 2 with HCl 37% to
give a white solid that was filtered, washed with water and dried.
Yield 91%. 24 g.
[0665] Analytical data: m.p. 175.degree. C.-180.degree. C. (lit.
175.degree. C.).
[0666] .sup.1H NMR (DMSO-d.sub.6) 12.5 (1H, br); 7.31 (1H, br);
6.91 (1H, br); 6.87 (1H, d, J=8.4 Hz); 4.23 (1H, q, J=7.7 Hz);
2.56-2.36 (2H, m); 1.38 (9H, s).
Step 2: N-[(1,1-dimethylethoxycarbonyl)amino]-L-asparagine, benzyl
ester
##STR00647##
[0668] The compound was prepared according to Bioorg. Med. Chem., 6
(1998) 1185-1208.
N-[(1,1-dimethylethoxycarbonyl)amino]-L-asparagine (20.7 g, 89.1
mmol, 1 eq.), of Step 1, was dissolved in methanol (500 ml) and
cesium carbonate (15.97 g, 49 mmol, 0.55 eq.) was added. The
solvent was evaporated to give a white solid that was dissolved in
N,N-dimethylformamide (200 ml). To the suspension, benzyl bromide
(11.6 ml, 98 mmol, 1.1 eq.) was added dropwise and the mixture was
stirred overnight. The solvent was reduced under reduced pressure,
water (300 ml) was added and the mixture extracted with ethyl
acetate (200 ml), washed with brine (50 ml) and the solvent removed
under reduced pressure to give a crude that was suspended in
n-hexane (160 ml), filtered and dried under vacuum to give 14.68 g
of white solid. Yield 51%.
[0669] Analytical data: m.p. 113.degree.-115.degree. C.
[0670] .sup.1H NMR (DMSO-d.sub.6) 7.35 (6H, m); 7.13 (1H, d, J=7.9
Hz); 6.94 (1H, br s); 5.10 (2H, s); 4.39 (1H, q, J=7.4 Hz); 2.6-2.4
(2H, m); 2.03 (2H, t, J=7.3); 1.37 (9H, s).
Step 3: 3-Amino-2-S-[(1,1-dimethylethoxycarbonyl)amino]-propionic
acid, benzyl ester
##STR00648##
[0672] N-[(1,1-dimethylethoxycarbonyl)amino]-L-asparagine, benzyl
ester, (2 g, 6.3 mmol, 1 eq.), of Step 2, was dissolved in
acetonitrile (80 ml) and water (80 ml). The solution was cooled to
0.degree.-5.degree. C. and iodobenzene diacetate (3 g, 9.3 mmol,
1.5 eq.) was added portionwise. The mixture was stirred at
0.degree. C. for 30', then at r.t. for 4 h. The organic solvent was
removed under vacuum, diethyl ether and HCl 1N were added. The
aqueous layer was separated and extracted with dichloromethane (100
ml) and sodium bicarbonate (3.5 g). The organic solvent was dried
over sodium sulphate anhydrous, evaporated under reduced pressure
to give 0.65 g of colourless oil. Yield 36%
[0673] Analytical data:
[0674] .sup.1H NMR (DMSO-d.sub.6) 7.45-7.20 (7H, m); 7.20 (1H, d,
J=7.7 Hz); 5.13 (2H, AB q, J=12.8); 4.01 (1H, m); 2.80 (2H, m);
1.38 (9H, s).
Example G.6
(2S)-2-[(1,1-dimethylethoxycarbonyl)amino]-3-[(4-methylbenzoyl)amino]propa-
noic acid
##STR00649##
[0675] Step 1:
2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(4-methylbenzoylamino)propionic
acid, benzyl ester
##STR00650##
[0677] 3-Amino-2-S-[(1,1-dimethylethoxycarbonyl)amino]-propionic
acid, benzyl ester, (690 mg, 2.34 mmol, 1 eq.), of Example G.5, was
dissolved in DMF dry (20 ml) and TBTU (900 mg, 2.98 mmol, 1.2 eq.)
was added. The mixture was stirred at r.t. for 10', cooled to
0.degree.-5.degree. C. with ice bath and NMM (0.51 ml, 4.68 mmol, 2
eq.) and 4-methyl benzoic acid (380 mg, 2.81 mmol, 1.2 eq.) were
added. The mixture was stirred at r.t. for 3 h, poured in water
(100 ml) and extracted with ethyl acetate (100 ml). The organic
layer was washed with a solution of citric acid 2% (50 ml), sodium
bicarbonate 2% (50 ml), NaCl 2% (50 ml), dried over sodium sulphate
anhydrous and evaporated at reduced pressure to give 1 g of oil.
Yield quantitative.
[0678] Analytical data:
[0679] .sup.1H NMR (DMSO-d.sub.6) 8.46 (1H, br t, J=5.7 Hz); 7.70
(2H, d, J=8.0); 7.35-7.2 (8H, m); 5.07 (2H, s); 4.29 (1H, m); 3.67
(1H, m); 3.58 (1H, m); 2.36 (3H, s); 1.37 (9H, s).
Step 2:
(2S)-2-[(1,1-dimethylethoxycarbonyl)amino]-3-(4-methylbenzoylamino-
)propionic acid
##STR00651##
[0681]
2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(4-methylbenzoylamino)-pr-
opionic acid, benzyl ester, (930 mg, 2.25 mmol), of Step 1, was
dissolved in methanol (25 ml) and Pd/C 10% (90 mg) was added. The
mixture was hydrogenated at atmospheric pressure for 1 h. Pd/C was
filtered and the solution was evaporated under reduced pressure to
give 650 mg of white foam. Yield 86%. Analytical data:
[0682] .sup.1H NMR (DMSO-d.sub.6): 12.5 (1H, br); 8.40 (1H, t,
J=5.7 Hz); 7.71 (2H, d, J=8.05 Hz), 7.27 (2H, d, J=8.05 Hz); 7.09
(1H, d, J=7.9), 4.17 (1H, m); 3.57 (2H, m); 2.35 (3H, s); 1.37 (9H,
m).
Example G.7
2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(hexanoylamino)propionic
acid
##STR00652##
[0683] Step 1:
2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(hexanoylamino)propionic
acid, benzyl ester
##STR00653##
[0685] Hexanoic acid (450 mg, 3.87 mmol, 1.2 eq.) was dissolved in
DMF dry (15 ml) and TBTU (1.24 g, 3.87 mmol, 1.2 eq.) was added,
the mixture was stirred at r.t. for 20', then was cooled to
0.degree.-5.degree. C. with ice bath.
3-amino-2-S-[(1,1-dimethylethoxycarbonyl)amino]propionic acid,
benzyl ester, (950 mg, 3.22 mmol, 1 eq.), of Example G.5, and NMM
(1.06 ml, 9.61 mmol, 2.5 eq.) were added. The mixture was stirred
at r.t. overnight, poured in water (150 ml) and extracted with
ethyl acetate (100 ml). The organic layer was washed with a
solution of citric acid 2% (50 ml), sodium bicarbonate 2% (50 ml),
NaCl 2% (50 ml), dried over sodium sulphate anhydrous and
evaporated at reduced pressure to give a crude that was purified by
silica gel column chromatography (eluent: n-hexane/ethyl acetate
2/1, R.f=0.52) 0.5 g of colourless oil.
[0686] Yield 40%.
[0687] Analytical data:
[0688] .sup.1H NMR (DMSO-d.sub.6).
[0689] .delta..sub.H: 7.87 (1H, br t, J=6.2 Hz); 7.35 (5H, m); 7.14
(1H, d, J=8.2); 5.07 (2H, s); 4.14 (1H, m); 3.37 (2H, m); 2.00 (2H,
t, J=7.1); 1.43 (2H, m); 1.36 (9H, s); 1.3-1.1 (4H, m); 0.83 (3H,
t, J=7.1 Hz)
Step 2:
2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(hexanoylamino)propionic
acid
##STR00654##
[0691]
2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(hexanoylamino)propionic
acid, benzyl ester (500 mg, 1.27 mmol), of Step 1, was dissolved in
methanol (15 ml) and Pd/C 10% (50 mg) was added. The mixture was
hydrogenated at atmospheric pressure for 1 h. Pd/C was filtered and
the solution was evaporated under reduced pressure to give 300 mg
of white solid. Yield 78%.
[0692] Analytical data: m.p. 123.degree.-125.degree. C.
[0693] .sup.1H NMR (DMSO-d.sub.6).
[0694] .delta..sub.H: 12.6 (1H, br); 7.84 (1H, br t); 6.87 (1H, d,
J=7.5 Hz); 4.00 (1H, m); 3.32 (2H, m); 2.04 (2H, t, J=7.5); 1.47
(2H, m); 1.38 (9H, s); 1.3-1.1 (4H, m); 0.85 (3H, t, J=7.1 Hz)
Example G.8
2-S-tert-butoxycarbonylamino-3-(4-fluorosulfonylamino)propionic
acid
##STR00655##
[0695] Step 1:
2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(4-fluorosulfonylamino)propioni-
c acid, benzyl ester
##STR00656##
[0697] 3-Amino-2-S-[(1,1-dimethylethoxycarbonyl)amino]propionic
acid, benzyl ester (1.25 g, 4.24 mmol, 1 eq.), of Example G.5, was
dissolved in dichloromethane dry (20 ml) and the solution was
cooled to 0.degree.-5.degree. C., under nitrogen. TEA (0.65 ml,
4.67 mmol, 1.1 eq.) and 4-fluoro-sulfonylchloride (0.9 g, 4.67
mmol, 1.1 eq.) in dichloromethane dry (10 ml) were added. The
mixture was stirred at r.t. for 1 h, evaporated under reduced
pressure and diethyl ether (25 ml) was added and a white solid was
obtained that was filtered and dried under vacuum to give 1.89 g of
product.
[0698] Yield 99%.
[0699] Analytical data: m.p. 105.degree.-107.degree. C. TLC silica
gel (eluent: n-hexane/ethyl acetate 1/1, R.f=0.55).
[0700] .sup.1H NMR (DMSO-d.sub.6).
[0701] .delta..sub.H: 7.91 (1H, t, J=6.2 Hz); 7.85 (2H, dd, J=5.3,
8.8); 7.43 (2H, t, J=8.8); 7.35 (5H, m); 7.15 (1H, d, J=8.2); 5.09
(2H, s); 4.14 (1H, m); 3.10 (2H, m); 1.36 (9H, s).
Step 2:
2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(4-fluorosulfonylamino)p-
ropionic acid
##STR00657##
[0703]
2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(4-fluorosulfonylamino)pr-
opionic acid, benzyl ester (1.8 g, 3.98 mmol), of Step 1, was
dissolved in methanol (30 ml) and Pd/C 10% (180 mg) was added. The
mixture was hydrogenated at atmospheric pressure for 1 h. Pd/C was
filtered and the solution was evaporated under reduced pressure to
give 1.39 g of colourless oil. Yield 97%.
[0704] Analytical data:
[0705] .sup.1H NMR (DMSO-d.sub.6).
[0706] .delta..sub.H: 12.7 (1H, br); 7.83 (2H, dd, J=5.3, 8.8);
7.78 (1H, br t, J=5.5); 7.42 (2H, t, J=8.8); 6.87 (1H, d, J=8.6);
3.99 (1H, m); 3.03 (2H, m); 1.36 (9H, s).
Example G.9
2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(3,4-dimethoxyphenylacetamido)-p-
ropionic acid
##STR00658##
[0707] Step 1:
2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(3,4-dimethoxyphenylacetamido)--
propionic acid, benzyl ester
##STR00659##
[0709] 3,4-Dimethoxy-phenylacetic acid (720 mg, 3.66 mmol, 1.2 eq.)
was dissolved in DMF dry (20 ml) and TBTU (1.17 g, 3.66 mmol, 1.2
eq.) was added, the mixture was stirred at r.t. for 20', then was
cooled to 0.degree.-5.degree. C. with ice bath.
3-amino-2-S-tert-butoxycarbonylamino-propionic acid, benzyl ester
(0.9 g, 3.05 mmol, 1 eq.), of Example G.5, and NMM (1.0 ml, 9.15
mmol, 2.5 eq.) were added. The mixture was stirred at 0.degree. C.
for 2 h, then poured in water (200 ml) and extracted with ethyl
acetate (100 ml). The organic layer was washed with the following
solutions: citric acid 2% (20 ml), sodium bicarbonate 2% (20 ml),
NaCl 2% (20 ml), dried over sodium sulphate anhydrous and
evaporated at reduced pressure to give a crude that was purified by
silica gel chromatography (eluent: n-hexane/ethyl acetate 1/1,
R.f=0.57) to give 1 g of colourless oil. Yield 69%.
[0710] Analytical data: .sup.1H NMR (DMSO-d.sub.6). .delta..sub.H:
8.02 (1H, t, J=5.7 Hz); 7.34 (5H, m); 7.17 (1H, d, J=7.7); 6.82
(2H, m); 6.71 (1H, dd, J=1.5, 8.2); 5.03 (2H, s); 4.14 (1H, m);
3.71 (3H, s); 3.69 (3H, s); 3.39 (2H, m); 1.36 (9H, s).
Step 2:
2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(3,4-dimethoxyphenylacet-
amido)-propionic acid
##STR00660##
[0712]
2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(3,4-dimethoxyphenylaceta-
mido)-propionic acid, benzyl ester (1 g, 2.1 mmol), of Step 1, was
dissolved in methanol (30 ml) and Pd/C 10% (10 mg) was added. The
mixture was hydrogenated at atmospheric pressure for 1 h. Pd/C was
filtered and the solution was evaporated under reduced pressure to
give 0.73 g of white foam. Yield 91%.
[0713] Analytical data: .sup.1H NMR (DMSO-d.sub.6). .delta..sub.H:
12.7 (1H, br); 8.06 (1H, t, J=5.9 Hz); 7.00 (1H, d, J=8.05); 6.91
(2H, m); 6.80 (1H, dd, J=1.5, 8.4); 4.08 (1H, m); 3.80 (3H, s);
3.78 (3H, s); 3.5-3.3 (2H, m); 1.36 (9H, s).
Example G.10
2-[(1,1-dimethylethoxycarbonyl)amino]-3-(3-phenylureido)propionic
acid
##STR00661##
[0714] Step 1:
2-[(1,1-dimethylethoxycarbonyl)amino]-3-(3-phenylureido)propionic
acid, benzyl ester
##STR00662##
[0716] 3-Amino-2-S-[(1,1-dimethylethoxycarbonyl)amino]propionic
acid, benzyl ester (1.14 g, 3.87 mmol, 1 eq.), of Example G.5, was
dissolved in dichloromethane (20 ml) at r.t., The solution was
cooled to 0.degree.-5.degree. C. and phenyl isocyanate (0.42 ml,
3.87 mmol, 1 eq.) in dichlorometane (5 ml) was added dropwise. The
solution was stirred at r.t. for 1 h, evaporated under reduced
pressure and purified by silica gel chromatography (eluent
n-hexane/ethyl acetate 1/1) to give 0.71 g of glassy solid that was
suspended in diethyl ether to give a white solid. Yield 44%.
Analytical data: TLC silica gel (eluent n-hexane/ethyl acetate 1/1
R.f.=0.44), m.p. 48.degree.-50.degree. C.
[0717] .sup.1H NMR (DMSO-d.sub.6). .delta..sub.H: 8.68 (1H, s);
7.4-7.27 (8H, m); 7.22 (2H, t, J=8.2 Hz); 6.90 (1H, t, J=7.3); 6.26
(1H, t, J=5.7); 5.11 (2H, s); 4.12 (1H, m); 3.58 (1H, m); 3.28 (1H,
m); 1.38 (9H, s).
Step 2:
2-[(1,1-dimethylethoxycarbonyl)amino]-3-(3-phenylureido)propionic
acid
##STR00663##
[0719]
2-S-[(1,1-dimethylethoxycarbonyl)amino]-3-(3-phenylureido)propionic
acid, benzyl ester (0.7 g, 1.7 mmol), of Step 1, was dissolved in
methanol (25 ml) and Pd/C 10% (70 mg) was added. The mixture was
hydrogenated at atmospheric pressure for 1 h. Pd/C was filtered and
the solution was evaporated under reduced pressure to give 0.47 g
of desired product. Yield 87%.
[0720] Analytical data: .sup.1H NMR (DMSO-d.sub.6). .delta..sub.H:
12.6 (1H, br); 8.66 (1H, s); 7.37 (2H, d, J=8.1 Hz); 7.21 (2H, t,
J=7.50); 7.08 (1H, d, J=7.9); 6.89 (1H, t, J=7.3); 6.21 (1H, t,
J=5.9); 3.98 (1H, m); 3.54 (1H, m); 3.22 (1H, m); 1.38 (9H, s).
Example G.11
Synthesis of Further Compounds
[0721] The following compounds can be prepared starting from
3-amino-2-S-[(1,1-dimethylethoxycarbonyl)amino]propionic acid,
benzyl ester of Example G.5, with the methods described in Step 1
and Step 2 of Examples G.6-G.10.
TABLE-US-00031 G.11.1 2-[(1,1- dimethylethoxy- carbonyl)amino]-3-
(acetamido)propionic acid. ##STR00664## G.11.2 2-[(1,1-
dimethylethoxy- carbonyl)amino]- 3-(9-fluorenyl- methyloxy-
carbamoyl)) propionic acid. ##STR00665## G.11.3 2-[(1,1-
dimethylethoxy- carbonyl)amino]- 3-(3-pentylureido) propionic acid.
##STR00666## G.11.4 2-[(1,1- dimethylethoxy- carbonyl)amino]-3-
(methanesolfonamido) propionic acid. ##STR00667## G.11.5 2-[(1,1-
dimethylethoxy- carbonyl)amino]-3- [(ethoxycarbonyl-
succinyl]-amide) ethyl]- propionic acid. ##STR00668##
Example G.12
2-[(1,1-Dimethylethoxycarbonyl)amino]-3-(3-benzyloxycarbonylamino)propioni-
c acid
##STR00669##
[0722] Step 1: N.sup.2-(tert-Butoxycarbonyl)-L-2,3-diaminopropionic
acid
##STR00670##
[0724] N-tert-butoxycarbonyl-L-asparagine, from step 1 of Example
G.5 or commercially available, (8 g, 0.034 mol, 1 eq.) was
suspended in ethyl acetate (72 ml), acetonitrile (72 ml) and water
(36 ml), and Iodobenzenediacetate (13.3 g, 0.041 mol, 1.2 eq.) was
added at 5.degree. C. The mixture was stirred at
10.degree.-25.degree. C. for 3-4 h, then a white solid came off.
The solid was filtered, washed with diethyl ether and dried under
vacuum to give a white powder. Yield 57%. 4 g.
[0725] Analytical data: m.p. 210.degree. C.-211.degree. C. Silica
gel (dichloromethane/methanol/acetic acid 5/3/1) Rf 0.5. .sup.1H
NMR (DMSO-d.sub.6) 4.15 (1H, t); 3.15 (2H, m); 1.45 (9H, s);
Step 2:
2-[(1,1-dimethylethoxycarbonyl)amino]-3-(3-benzyloxycarbonylamino)-
propionic acid
##STR00671##
[0727] N.sup.2-(tert-Butoxycarbonyl)-L-2,3-diaminopropionic acid,
from step 1, (3.8 g, 0.018 mol, 1 eq.) was dissolved in aqueous
sodium carbonate 10% (2.2 eq.) at 25.degree. C. and 1,4-dioxane (38
ml). To this solution, benzylchloroformate (3 ml, 0.020 mol, 1.1
eq.) was added dropwise and the solution was stirred at 25.degree.
C. for 3 h. At the end of the reaction, the mixture was poured in
water (100 ml) and washed with diethyl ether (100 ml). To the
aqueous solution, HCl 37% (6 ml) was added till pH 2 and the
obtained mixture was extracted with Ethyl Acetate (100 ml). The
organic layer was separated, washed with brine and dried over
sodium sulfate anhydrous. The solvent was removed under reduced
pressure to give a colourless oil that under vacuum gave a white
foam.
[0728] Yield 93%, 5.9 g.
[0729] Analytical data: silica gel (dichloromethane/methanol/acetic
acid 5/3/1) Rf 1.
[0730] .sup.1H NMR (DMSO-d.sub.6) 12.6 (1H br s); 7.35 (5H m); 6.94
(1H, d); 5 (2H, s); 4.1 (2H, m); 1.4 (9H, s).
Example G.13
2-(tert-Butoxycarbonilamino)-3-pyrazol-1-yl-propionic acid
##STR00672##
[0732] The intermediate was prepared according to the procedure
described in Vederas, J. Am. Chem. Soc., 1985, 107, 7105-7109.
Example G.14
1-Methanesulfonyl-piperidine 4-carboxylic acid
##STR00673##
[0733] Step 1:
1-[(1,1-Dimethylethoxycarbonyl)amino]-piperidine-4-carboxylic
acid
##STR00674##
[0735] Piperidine-4-carboxylic acid (5 g, 38.7 mmol, 1 eq.) was
dissolved in sodium carbonate solution (4.5 g, 42.6 .mu.mol, 2.2
eq.), 70 ml, and 1,4-dioxane (30 ml). A solution of
di-tert-butyldicarbonate (9.3 g, 42.61 mmol, 1.1 eq.) in
1,4-dioxane (40 ml) was added dropwise and the resulting mixture
was stirred overnight at room temperature. The organic solvent was
removed under reduced pressure and the resulting solution was
acidified with HCl 37% till pH 2. The obtained suspension was
filtered, the white solid washed with diethyl ether (5 ml). The
mother liquor has been extracted with ethyl acetate (120 ml) and
the previous solid was added. The organic solution was dried over
anhydrous sodium sulfate, evaporated under reduced pressure to give
a white solid that was dried at 80.degree. C. under vacuum to give
the title compound. Yield 93%, 8.2 g.
[0736] Analytical data: m.p. 133.degree.-135.degree. C.
[0737] .sup.1H NMR (DMSO-d.sub.6) 12.3 (1H br s); 3.85 (2H, d); 2.8
(2H, br); 2.35 (1H, t); 1.8 (2H, d); 1.4 (11H, m).
Step 2:
1-[(1,1-Dimethylethoxycarbonyl)amino]-piperidine-4-carboxylic acid
benzyl ester
##STR00675##
[0739]
1-[(1,1-Dimethylethoxycarbonyl)amino]-piperidine-4-carboxylic acid
(6 g, 26.16 mmol, 1 eq.), from step 1, was dissolved in methanol
(150 ml) and cesium carbonate (4.26 g, 13.08 mmol, 0.5 eq.) was
added. The mixture was stirred at room temperature for 2 h, the
solvent was removed under reduced pressure. The crude was dissolved
in DMF (100 ml) and benzylbromide (5.37 g, 31.39 mmol, 1.2 eq.) was
added dropwise. The mixture was stirred overnight at room
temperature and poured in water (300 ml), extracted with Ethyl
Acetate (900 ml) The organic layer was dried over anhydrous sodium
sulfate and evaporated under reduced pressure to give a white
solid.
[0740] Yield 95%, 7 g.
[0741] Analytical data:
[0742] .sup.1H NMR (DMSO-d.sub.6) 7.3 (5H m); 5.1 (2H, s); 3.85
(2H, d); 2.8 (2H, br); 2.65 (1H, t); 1.8 (2H, d); 1.4 (11H, m).
Step 3: Piperidine-4-carboxylic acid benzyl ester, hydrochloride
salt
##STR00676##
[0744]
1-[(1,1-Dimethylethoxycarbonyl)amino]-piperidine-4-carboxylic acid
benzyl ester (7 g, 21.0 mmol), from step 2, was dissolved in
1,4-dioxane (20 ml). To this solution, HCl 4N in 1,4-dioxane (7.8
ml, 300 ml, 12 eq.) was added and the resulting solution was
stirred overnight at room temperature. The solid was filtered,
suspended in n-hexane (50 ml), and filtered to give a white solid.
Yield 54%, 2.5 g.
[0745] Analytical data:
[0746] .sup.1H NMR (DMSO-d.sub.6) 8.9 (2H, br); 7.35 (5H, m); 5.1
(2H, s); 3.25 (2H, d); 2.9 (2H, t); 2.75 (1H, m); 2.0 (2H, m); 1.8
(2H, m).
Step 4: 1-Methanesulfonyl-piperidine-4-carboxylic acid benzyl
ester
##STR00677##
[0748] Piperidine-4-carboxylic acid benzyl ester, hydrochloride
salt (1 g, 3.9 mmol, 1 e.) from step 3, was dissolved in DMF (15
ml), Triethylamine (0.55 ml, 4 mmol, 1 eq.) and
methanesulfonylchloride were added. The mixture was stirred for 1 h
at room temperature, then was poured in water (20 ml). The aqueous
solution was extracted with Ethyl Acetate (90 ml) and the organic
layer was dried over anhydrous sodium sulfate, evaporated under
reduced pressure to give a colourless oil. Yield 78%, 0.9 g.
[0749] Analytical data:
[0750] .sup.1H NMR (DMSO-d.sub.6) 7.35 (5H, m); 5.1 (2H, s); 3.5
(2H, d); 2.8 (5H, m); 2.6 (1H, m); 2.0 (2H, m); 1.6 (2H, m).
Step 5: 1-Methanesulfonyl-piperidine 4-carboxylic acid
##STR00678##
[0752] 1-Methanesulfonyl-piperidine-4-carboxylic acid benzyl ester
(0.8 g, 26.7 mmol) from step 4, was dissolved in ethyl acetate (100
ml) and methanol (10 ml), Pd/C 10% (80 mg) was added and the
resulting mixture was hydrogenated at 1 bar. The catalyst was
filtered over celite, the solvent was removed under reduced
pressure to give a white solid. Yield 73%, 0.4 g
[0753] Analytical data:
[0754] .sup.1H NMR (DMSO-d.sub.6) 12.4 (1H, br); 3.6 (2H, d); 2.9
(4H, m); 2.4 (1H, m); 2.0 (2H, m); 1.6 (2H, m).
Example G.15
(4-Methylphenyl)-ureido-sulfonylchloride
##STR00679##
[0756] This compound was prepared according to J. Med. Chem. 1996,
39, 1243-1252. Briefly, a solution of chlorosulfonylisocyanate
(1.62 g, 11.5 mmol, 1 eq.) was diluted in dry diethylether and the
resulting solution was cooled at -50.degree. C.<T<-40.degree.
C. To this solution, p-toluidine (1.23 g, 11.5 mmol, 1 eq.) was
added. The solution was stirred at -35.degree. C. for 10' and a
suspension was obtained. The solid was filtered and washed with
diethyl ether. Yield 80%, 2.3 g.
[0757] Analytical data: m.p. 127.degree.-129.degree. C.
[0758] .sup.1H NMR (DMSO-d.sub.6) 9.9 (1H, s); 7.3 (2H, d); 7.1
(2H, d); 2.25 (3H, s);
Example G.16
Isoxazole-5-carboxylic acid
##STR00680##
[0760] The desired carboxylic acid was prepared according to the
procedure by Wolfang et al., Synthesis, 1986, 69-70.
UTILITY
Compound Activity
[0761] The present compounds can inhibit proteasome activity. Table
F-1 below provides data related to several Example compounds of the
invention with respect to, for example, ability to inhibit
proteasome activity.
Methods and Compositions
[0762] Compounds of the present invention can inhibit the activity
of proteasome leading to the inhibition or blocking of a variety of
intracellular functions with which the proteasome is directly or
indirectly associated. For example, proteasome inhibitors can
modulate, such as induce, apoptosis in a cell. In some embodiments,
the compounds herein can kill tumor cells by induction of
apoptosis. Thus, the present compounds can be used to treat cancer,
tumors or other proliferative disorders.
[0763] In further embodiments, inhibition of proteasome function by
compounds of the invention can inhibit the activation or processing
of transcription factor NF-.kappa.B. This protein plays a role in
the regulation of genes involved in the immune and inflammatory
responses as well as in cell viability Inhibition of proteasome
function can also inhibit the ubiquitination/proteolysis pathway.
This pathway catalyzes, inter alia, selective degradation of highly
abnormal proteins and short-lived regulatory proteins. In some
embodiments, compounds of the invention can prevent the degradation
of p53 which is typically degraded by the ubiquitin-dependent
pathway. The ubiquitination/proteolysis pathway also is involved in
the processing of internalized cellular or viral antigens into
antigenic peptides that bind to MHC-I molecules. Thus, the
compounds of the invention can be used to reduce the activity of
the cytosolic ATP-ubiquitin-dependent proteolytic system in a
number of cell types.
[0764] Accordingly, the usefulness of such compounds can include
therapeutics, such as the treatment of various diseases or
disorders associated with proteasome. The methods include
administering a therapeutically effective amount of a compound of
the invention, or composition thereof, to a mammal, such as a human
having a disease or disorder associated with proteasome. The phrase
"therapeutically effective amount" refers to an amount sufficient
to prevent, alleviate, or ameliorate any phenomenon, such as a
cause or symptom, known in the art to be associated with the
disease or disorder.
[0765] Treatable diseases or disorders (abnormal physical
conditions) can be associated with either normal or abnormal
activities of proteasome, such as the regulation of apoptosis.
Numerous diseases or disorders that are associated with proteasome,
or that are desirably treated by induction of apoptosis, are known
and include, for example, various cancers and tumors including
those associated with skin, prostate, colorectal, pancreas, kidney,
ovary, mammary, liver, tongue, lung, and smooth muscle tissues.
Preferred tumors that can be treated with proteasome inhibitors
include, but are not limited to hematological tumors, such as, for
example, leukemias, lymphomas, non-Hodgkin lymphoma, myeloma,
multiple myeloma, as well as solid tumors such as, for example,
colorectal, mammary, prostate, lung, and pancreas tumors. In order
to elicit therapeutic effects, the proteasome inhibitors can be
administered to patients as single agents or in combination with
one or more antitumor or anticancer agent and/or radiotherapy.
Examples of other anti-tumor or anti-cancer agents which can be
advantageously administered concomitantly with a proteasome
inhibitor include but are not limited to, adriamycin, daunomycin,
methotrexate, vincristin, 6-mercaptopurine, cytosine arabinoside,
cyclophosphamide, 5-FU, hexamethylmelamine, carboplatin, cisplatin,
idarubycin, paclitaxel, docetaxel, topotecan, irinotecam,
gemcitabine, L-PAM, BCNU and VP-16. Methods for determining
apoptosis in vitro are well known in the art and kits are available
commercially. See for example the Apo-ONE.TM. Homogeneous
Caspase-3/7 Assay from Promega Corporation, Madison Wis., USA
(Technical Bulletin No. 295, revised 2/02, Promega
Corporation).
[0766] Further diseases or disorders associated with the proteasome
include accelerated or enhanced proteolysis that occurs in
atrophying muscles, such as is often associated with activation of
a nonlysomal ATP-requiring process involving ubiquitin. Accelerated
or enhanced proteolysis can be the result of any of numerous causes
including sepsis, burns, trauma, cancer, infection,
neurodegenerative diseases such as muscular dystrophy, acidosis, or
spinal/nerve injuries, corticosteroid use, fever, stress, and
starvation. Compounds of the invention can be tested for inhibition
of muscle wastage by any various procedures known in the art such
as by measuring urinary excretion of modified amino acid
3-methylhistidine (see, e.g., Young, et al., Federation Proc.,
1978, 37, 229).
[0767] Compounds of the present invention can be further used to
treat or prevent diseases or disorders associated with activity of
NF-.kappa.B including for example, human immunodeficiency virus
(HIV) infection and inflammatory disorders resulting from, for
example, transplantation rejection, arthritis, infection,
inflammatory bowel disease, asthma, osteoporosis, osteoarthritis,
psoriasis, restenosis, and autoimmune diseases. Accordingly, a
process that prevents activation of NF-.kappa.B in patients
suffering from such a disease would be therapeutically beneficial.
Inhibition of the NF-.kappa.B activity can be measured by using a
DNA binding assay such a described in Palombella, et al., Cell,
1994, 78, 773.
[0768] Those of ordinary skill in the art can readily identify
individuals who are prone to or suspected of suffering from such
diseases or disorders using standard diagnostic techniques.
Example A
Assay for Chymotrypsin-like Activity of 20S Human Erythrocyte
Proteasome (HEP)
[0769] Proteasome chymotrypsin-like activity of compounds of the
invention was assayed according to the following procedure.
[0770] In 96-well microtiter plates, 20S Human Erythrocyte
Proteasome (HEP), purchased from Immatics Biotechnologies Inc.,
Tubingen, Germany was plated at 0.2 .mu.g/mL (about 0.6 nM
catalytic sites) in 0.04% SDS 20 mM Tris buffer. A fluorimetric
substrate Suc-LLVY-AMC
(succinyl-Leu-Leu-Val-Tyr-7-amido-4-methylcoumarin), purchased from
Sigma Inc., St. Louis, Mo., USA was added to a final concentration
of 100 .mu.M from a stock solution of 10 mM in dimethylsulfoxide.
Reaction volumes were 100 .mu.l per well. After incubation for
various periods of time at 37.degree. C., the concentration of free
AMC (aminomethylcoumarin) was determined on a Perkin Elmer HTS 7000
Plus microplate reader, excitation 370 nM and emission 465 nM.
Proteasome activity was determined under conditions in which
substrate hydrolysis increased linearly with time and the change in
fluorescence signal was proportional to the concentration of free
AMC.
Example B
Assay for Activity of .alpha.-Chymotrypsin
[0771] In 96-well microtiter plates bovine .alpha.-chymotrypsin,
purchased from Sigma Inc., was plated at 10 ng/mL (about 2 .mu.M
catalytic sites) in 0.5 M NaCl 50 mM Hepes buffer. A fluorimetric
substrate Suc-AAPF-AMC
(succinyl-Ala-Ala-Pro-Phe-7-amido-4-methylcoumarin), purchased from
Sigma Inc., St. Louis, Mo., USA was added to a final concentration
of 25 uM from a stock solution of 10 mM in dimethylsulfoxide.
Reaction volumes were 100 .mu.l per well. After incubation for
various periods of time at room temperature, the concentration of
free AMC was determined on a Perkin Elmer HTS 7000 Plus microplate
reader, excitation 370 nM and emission 465 nM. .alpha.-Chymotrypsin
activity was determined under conditions in which substrate
hydrolysis increased linearly with time and the change in
fluorescence signal was proportional to the concentration of free
AMC.
Example C
Determination of IC.sub.50 Values for HEP and .alpha.-Chymotrypsin
Inhibitors
[0772] IC.sub.50 values are typically defined as the concentration
of a compound necessary to produce 50% inhibition of the enzyme's
activity. IC.sub.50 values are useful indicators of the activity of
a compound for its designated use. The proteasome inhibitors of the
invention can be considered active if they have IC.sub.50 values of
less than about 1 micromolar for inhibition of human erythrocyte
proteasome (HEP). In some embodiments, the inhibitors show some
specificity for HEP and the ratio of the IC.sub.50 for inhibition
of bovine .alpha.-chymotrypsin versus the IC.sub.50 for inhibition
of HEP, i.e, IC.sub.50 (.alpha.-Chymotripsin)/IC.sub.50 (HEP), is
greater then about 100.
[0773] Inhibition of the chymotrypsin-like activity of HEP and of
bovine .alpha.-chymotrypsin was determined by incubating the enzyme
with various concentrations of putative inhibitors for 15 minutes
at 37.degree. C. (or room temperature for .alpha.-chymotrypsin)
prior to the addition of substrate. Each experimental condition was
evaluated in triplicate, and replicate experiments were performed
for the inhibitors described herein.
[0774] Compounds of the present invention are considered active in
the above identified assay if their IC.sub.50 values for inhibition
of HEP are less than 1000 nanoMolar. Preferably compounds of the
present invention will have IC.sub.50 values for inhibition of HEP
less than 100 nanoMolar. More preferably compounds of the present
invention will have IC.sub.50 values for inhibition of HEP less
than 10 nanoMolar. Compounds of the present invention have
demonstrated, in the above identified assay, IC.sub.50 values for
inhibition of HEP less than 1000 nanoMolar.
Example D
Cellular Assay for Chymotrypsin-like activity of Proteasome in
Molt-4 Cell Line
[0775] The chymotrypsin-like activity of proteasome in Molt-4 cells
(human leukemia) was assayed according to the following procedure.
A brief description of the method was published previously (Harding
et al., J. Immunol., 1995, 155, 1767).
[0776] Molt-4 cells were washed and resuspended in HEPES-buffered
Saline (5.4 mM KCl, 120 mM NaCl, 25 mM Glucose, 1.5 mM MgSO.sub.4,
1 mM Na pyruvate, 20 mM Hepes) and plated in 96-well microtiter
white plates to a final concentration of 6.times.10.sup.6 cells/mL.
Then various 5.times. proteasome inhibitor concentrations (or
diluted DMSO for controls), prepared from 250.times.DMSO solutions
by diluting 50-fold using HEPES-buffered saline, were added to the
plate to a final 1.times. concentration. After 15 minutes
incubation at 37.degree. C., a fluorimetric cell permeable
substrate (MeOSuc-FLF-AFC)
(methoxysuccinyl-Phe-Leu-Phe-7-amido-4-trifluoromethylcoumarin)
purchased from Enzyme Systems Products, catalogue number AFC-88,
was added to each well at a final concentration of 25 .mu.M from a
stock solution of 20 mM in DMSO. Reaction volumes were 100 .mu.l
per well.
[0777] The concentration of free AFC was monitored every 1.5 min
for 30 min (22 cycles) on a Polastar Optima, BMG Labtechnologies
microplate reader, using an excitation wavelength of 390 nm and
emission wavelength of 520 nm. Proteasome activity was determined
under conditions in which substrate hydrolysis increased linearly
with time and the change in fluorescent signal was proportional to
the concentration of free AFC.
Example E
Determination of EC.sub.50 Values for Proteasome Inhibitors in
MOLT-4 Cell Line
[0778] EC.sub.50 values are typically defined as the concentration
of a compound required to produce an inhibition of the enzyme's
activity halfway between the minimum and the maximum response (0%
and 85-90% respectively for this assay). EC.sub.50 values are
useful indicators of the activity of a compound for its designated
use. The compounds of the invention can be considered active if
they have an EC.sub.50 of less than about 10 micromolar.
[0779] Inhibition of chymotrypsin-like activity of proteasome in
Molt-4 cells was determined by incubating cells with various
concentrations of putative inhibitors for 15 minutes at 37.degree.
C. prior to the addition of substrate. Each experimental condition
was evaluated in triplicate, and replicate experiments were
performed for the inhibitors described herein.
[0780] Compounds of the present invention are considered active in
the above identified assay if their EC.sub.50 values for proteasome
inhibition in MOLT-4 are less than 10 microMolar. Preferably
compounds of the present invention will have EC.sub.50 values for
proteasome inhibition in MOLT-4 less than 2 microMolar. More
preferably compounds of the present invention will have EC.sub.50
values for proteasome inhibition in MOLT-4 less than 200 nanomolar.
Compounds of the present invention have demonstrated, in the above
identified assay, EC.sub.50 values for proteasome inhibition in
MOLT-4 cells of less than 10 microMolar.
Example F
Assay for Trypsin-like Activity of the Proteasome
[0781] The trypsin-like activity of human proteasome can be assayed
as described above with the following modifications. Reactions can
be carried out in Tris-glycerol buffer (pH 9.5) supplemented with 1
mM 2-mercaptoethanol, and the substrate can be a fluorogenic
substrate such as benzyloxycarbonyl-Phe-Arg-AMC (100 .mu.M).
[0782] After incubation for various periods of time at 37.degree.
C., the concentration of free AMC can be determined on a Fluoroskan
II spectrofluorimeter with an excitation filter of 390 nm and an
emission filter of 460 nm. Protease activity can be determined
under conditions in which substrate hydrolysis increases linearly
with time and the change in fluorescence is proportional to the
concentration of free AMC.
Example G
In Vivo Inhibition of Cellular Muscle Breakdown
[0783] The effect of inhibitors on the unweighting atrophy of the
soleus muscle in juvenile rats can be determined by, for example,
the procedures described in Tischler, Metabolism, 1990, 39, 756.
For example, juvenile female Sprague-Dawley rats (80-90 g) can be
tail-cast, hind limb suspended as described in Jaspers, et al., J.
Appl. Physiol., 1984, 57, 1472. The animal's hind limbs can be
elevated above the floor of the cage with each animal housed
individually. Animals can have free access to food and water, and
can be weighed at the time of suspension and at time of
termination. During the suspension period the animals can be
checked daily to ensure that their toes are not touching the floor
of the cage, and that there is no swelling of the tail due to the
cast.
Experimental Design--Part 1
[0784] Each experiment can begin with the suspension of 20 rats
which are randomly divided into 4 groups of 5 animals each. Group A
can be suspended for 2 days, providing baseline data to approximate
the soleus muscle size in other animals suspended for longer times.
Average body weights for the groups at the outset of the study can
be compared and used as a correction factor for body size
differences. Group B can be a second control group which has the
soleus of one limb treated with an aqueous solution of mersalyl
after two days of unweighting, to demonstrate the ability to slow
muscle atrophy during unweighting, for each group of animals. At 2
days after unweighting commences, an aqueous solution of mersalyl
(200 nM; 4 .mu.L/100 g initial body wt) can be injected into one
soleus. The contralateral muscle can be injected with a similar
volume of 0.9% saline ("Vehicle"). The animals can be maintained
under Innovar-vet (10 .mu.L/100 g body wt) tranquilization during
the in situ injection procedure. After the injections, the animals
can be suspended for an additional 24 hours and the soleus can be
removed. Groups C and D for each experiment can be used for testing
each of two different embodiments of the disclosed compounds.
Animals can be treated as in group B, except that 1 mM proteasome
inhibitor, contained in dimethysulfoxide (DMSO), can be injected
into the soleus of one leg and DMSO only into the contralateral
soleus. Thus each experiment consists of two control groups and the
testing of proteasome inhibitors of the invention. The completion
of five such experiments with different pairs of inhibitors
provides for an "n" value of 10 for testing each inhibitor and each
can be tested in two different shipments of animals.
Processing of the Soleus Muscle--Part 1
[0785] After the animal is sacrificed, the soleus can be excised,
trimmed of fat and connective tissue, and carefully weighed. The
muscle can then homogenized in 10% trichloroacetic acid (TCA) and
the precipitated protein pelleted by centrifugation. The pellet can
then be washed once with 10% TCA and once with ethanol:ether (1:1).
The final pellet can be solubilized in 4 ml of 1N sodium hydroxide.
The sample can be then analyzed for protein content by the biuret
procedure, using albumin as a standard.
Data Analysis--Part 1
[0786] The effect of inhibitors on total muscle protein content can
be examined primarily by paired comparison with the untreated
contralateral muscle. The ratio of contents can be calculated and
then analyzed statistically by analysis of variance ("ANOVA"). The
left leg can always be the treated leg so that the protein content
ratios can be compared to the non-treated control animals as well.
In this way, a significant difference can be shown by comparing the
protein content of the two legs, as well as the relative
effectiveness of the tested inhibitors. A paired student test can
also be performed for the effect of each separate treatment. The
non-treated control data also provide an estimate of protein
content of day 2. This allows approximation of the protein changes
over the 24 hours of treatment for each of the Groups B, C, and
D.
Experimental Design--Part 2
[0787] Each experiment can consist of 10 animals with groups of 5
animals being tested with one of the inhibitors for its effect on
protein synthesis. Control animals are not needed for this aspect
of the study as the contralateral DMSO-treated muscle serves as the
paired control for the inhibitor-treated muscle. Each group can be
injected as described for groups C and D in part 1. Twenty-four
hours after the in situ treatment the fractional rate of protein
synthesis can be analyzed in both soleus muscles. Each muscle can
be injected with a 0.9% saline solution (3.5 .mu.l/100 g final body
wt) containing .sup.3H-phenylalanine (50 mM; 1 .mu.Ci/.sup.ml).
Fifteen minutes later the middle two-thirds of the muscle can be
excised and the muscle can be processed as described below.
Processing of the Soleus Muscle--Part 2
[0788] The muscle can be first washed for 10 minutes in 0.84%
saline containing 0.5 mM cycloheximide, to terminate protein
synthesis, and 20 mM cycloleucine, to trap phenylalanine in the
cell. The muscle can then be homogenized in 2.5 mL of ice-cold 2%
perchloric acid. The precipitated protein can be pelleted by
centrifugation. One aliquot of the supernatant can be taken for
liquid scintillation counting and another aliquot can be processed
for conversion of phenylalanine to phenethylamine to determine the
soluble phenylalanine concentration fluorometrically. See, e.g.,
Garlick, et al., Biochem. J., 1980, 192, 719. These values can
provide the intracellular specific activity. The specific activity
of phenylalanine in the muscle protein can be determined after
hydrolyzing the protein by heating in 6N HCl. The amino acids
released can be solubilized in buffer. One aliquot can be taken for
scintillation counting and another for analysis of phenylalanine as
for the supernatant fraction. The fractional rate of protein
synthesis can be calculated as: protein specific
activity/intracellular specific activity.times.time.
Data Analysis--Part 2
[0789] Analyses of protein synthesis can be on a paired basis for
each inhibitor. Student paired t test comparisons of the
contralateral muscles can determine whether there is any effect of
the inhibitor on protein synthesis. Protein breakdown can be
calculated approximately as the fractional rate of protein
synthesis (from part 2) plus the fractional rate of protein
accretion (from part 1), where protein loss yields a negative value
for protein accretion.
[0790] Qualitatively the ability of inhibitors to slow protein loss
without affecting protein synthesis indicates a slowing of protein
degradation.
Example H
In vivo Investigation of Anti-Tumor Activity
Materials
[0791] The proteasome inhibitors used for in vivo studies can be
formulated in an appropriate medium for intravenous (iv) or oral
(po) administration. For example, for the iv administration the
compounds can be administered dissolved in 0.9% NaCl, or in
mixtures of 0.9% NaCl, solutol HS15 and dimethylsulfoxide, for
example in the ratio 87:10:3 (v:v:v), respectively.
Cell Lines
[0792] The following human and murine tumor cell lines of different
histological origine can be used to test the antitumor activity of
the compounds of the invention: H460 (human, lung), A2780 (human,
ovary), PC-3 (human, prostate), LoVo (human, colon), HCT116 (human,
colon), BXPC3 (human, pancreatic), PANC-1 (human, pancreatic), MX-1
(human, mammary), MOLT (human, leukemia), multiple myeloma (human,
myeloma), YC8 (murine, lymphoma), L1210 (murine, leukemia), 3LL
(murine, lung).
Animal Species
[0793] 5-6 weeks immunocompetent or immunodeprived mice are
purchased from commercial sources, for example from Harlan
(Correzzana, Mi Italy). CD1 nu/nu mice are maintained under sterile
conditions; sterilized cages, bedding, food and acidified water are
used.
Tumor Cell Implantation and Growth
[0794] Solid tumor models of different hystotype (lung, ovary,
breast, prostate, pancreatic, colon) can be transplanted
subcutaneously (sc.) into the axillary region of immunocompetent
mice (murine models) or in immunodeprived mice (human models).
Human tumor cell lines, originally obtained from ATCC, can be
adapted to grow "in vivo" as solid tumor from "in vitro
culture".
[0795] Hematological human or murine tumor models can be
transplanted into different sites (iv, ip, is or sc) in
immunocompetent mice (murine tumors) or in immunodeprived mice
(human leukemia, lymphoma and myeloma models), according to their
highest tumor take.
Drug Treatment
[0796] Mice bearing solid (staged) or hematological tumors are
randomized in experimental groups (10 mice/group). For solid
tumors, an average tumor weight of 80-100 mg for each group is
considered to start the treatment; mice with the smallest and
largest tumors are discarded.
[0797] Experimental groups are randomly assigned to the drug
treatment and to the control group. Animals can be treated iv or
orally, depending on the oral bioavailability with the compounds
following different treatment schedules: iv weekly or twice weekly,
or by daily oral administration.
[0798] On solid tumor models, drug treatment can begin when the
tumor size ranges between 80-100 mg after tumor transplantation
(Day 0).
[0799] The compounds can be administered in a volume of 10 mL/Kg
body weight/mouse in the appropriate solvent.
Parameters of Antitumor Activity
[0800] The following parameters can be assessed for the evaluation
of the antitumor activity: [0801] growth of primary solid tumor; in
each mouse is monitored by caliper measurement twice weekly; [0802]
survival time of treated mice as compared to control mice [0803]
twice weekly body weight evaluation of individual mice.
[0804] The tumor growth inhibition, TWI % (percentage of primary
tumor growth inhibition in comparison with vehicle treated control
groups) or the Relative tumor growth inhibition, RTWI % in case of
staged tumors, is evaluated one week after the last drug treatment
and the Tumor weight (TW) can be calculated as follows:
TW=1/2ab.sup.2
where a and b are long and short diameters of the tumor mass in
mm.
[0805] The antitumor activity can be determined as tumor weight
inhibition (TWI %), which is calculated according to the
formula:
TWI % = 100 - mean TW treated mean TW controls .times. 100
##EQU00001##
[0806] The RTWI % (relative percentage of primary tumor growth
inhibition in comparison with vehicle treated control groups) is
evaluated one week after the last drug treatment, according to the
following formula:
RTWI % = 100 - mean RV of treated mice mean RV of controls mice
.times. 100 ##EQU00002## where RV = Vt ( tumor weight on day t ) V
O ( initial tumor weight at the outset of treatment )
##EQU00002.2##
[0807] The Percent of Tumor Regression can be calculated as
regressions in terms of relative tumor weight, determined as tumor
weight at given day divided by initial tumor weight at the outset
the experiment.
[0808] On haematological tumour models the antitumor activity can
be determined as percentage increase of the median survival time of
mice expressed as the ratio (T/C %) of the median survival time of
the treated group (T) to that of the control group (C). Animals
which are tumour-free at the end of the experiment (60 days after
transplantation) are excluded from the calculation and considered
as long term survivors (LTS).
Evaluation of Toxicity in Tumor Bearing Mice
[0809] Toxicity can be evaluated daily on the basis of the gross
autopsy findings and the weight loss. Mice are considered to have
died of toxicity when death occurs before the death of vehicle
treated control animals, or when significant body weight loss
(>20%), and/or spleen and liver size reduction are observed.
[0810] The BWC % (Body weight change %) is assessed as follow:
100-(mean body weight of mice at given day/mean body weight at
start of treatment).times.100. This value is determined one week
after the last treatment with the test compound.
Example K
In Vitro Viability of Cells
[0811] The IC.sub.50 values measuring in vitro viability of cells
in the presence of test compounds can be determined according to
the following procedure. Cells can be seeded in 96-well plates at
varying densities and then assayed using the Calcein-AM viability
assay after 24 hours to determine the optimal final density for
each cell type. Cells can then be seeded in 96-well plates at the
determined density in 100 .mu.L of an appropriate cell media known
to one skilled in the art.
[0812] Serial dilutions of test compounds can be made so that the
concentrations are twice the desired concentration to be evaluated.
When 100 .mu.L of the dilution is then added to the cells plated in
100 .mu.L of media, a final concentration of, for example, 0, 11.7,
46.9, 187.5, 375, and 750 nM can be obtained. Compounds can be
added to the plates three to four hours after seeding the cells,
then the plates can be incubated at 37.degree. C. for the desired
time point (e.g., one, two, or three days).
[0813] Calcein-AM viability assays can be conducted at the desired
time points as follows. Media can be aspirated using a manifold and
metal plate to leave approximately 50 .mu.L/well. The wells can be
washed three times with 200 .mu.L DPBS, aspirating each time with
the manifold to leave 50 .mu.L/well. A 8 .mu.M solution of
Calcein-AM in DPBS can be prepared and 150 .mu.L can be added to
each well. The plates can then be incubated at 37.degree. C. for 30
minutes. After incubation, calcein can be aspirated with the
manifold and cells can be washed with 200 .mu.L DPBS as before.
After final aspiration, fluorescence can be measured using a
Cytofluor 2300 fluorescence plate reader. Negative controls can
contain media and no cells, and experiments can be conducted in
triplicate.
Example L
Kinetic Experiments In Vitro
[0814] Compounds of the invention can be tested for proteasome
inhibitory activity using a protocol described in Rock, et al.,
Cell, 1994, 78, 761. According to this procedure, dissociation
constants (K.sub.i) for the equilibrium established when proteasome
and test compound interact to form a complex. The reactions can be
carried out using SDS-activated 20S proteasome from rabbit muscle,
and the proteasome substrate can be Suc-LLVY-AMC.
Example M
Inhibition of Activation of NF-.kappa.B
[0815] Compounds of the invention can be tested for inhibiting the
activity of NF-.kappa.B by carrying out the assay described in
Palombella, et al., Cell, 1994, 78, 773). For example, MG63
osteocarcinoma cells can be stimulated by treatment with
TNF-.alpha. for designated times. Whole cell extracts can be
prepared and analyzed by electrophoretic mobility shift assays
using the PRDII probe from the human IFN-.beta. gene promoter.
Example N
Compound Activity
[0816] Using the assays of Example C and Example E above the
following Table F-1 demonstrates the utility of compounds of the
invention for proteasome inhibition. In the following Tables, for
the inhibition of HEP, Example C, compounds of the present
invention with a "+" are less than 1000 nM; compounds of the
present invention with a "++" are less than 100 nM; and compounds
of the present invention with a "+++" are less than 10 nM in
IC.sub.50 for HEP inhibition. In the following Tables, for the
inhibition of MOLT4, Example E, compounds of the present invention
with a "+" are less than 10000 nM; compounds of the present
invention with a "++" are less than 2000 nM; and compounds of the
present invention with a "+++" are less than 200 nM in EC.sub.50
for HEP inhibition. Where ">+" occurs activity was greater than
the limits of the assay. Where no IC.sub.50 value or EC.sub.50
value is represented, data has yet to be determined
TABLE-US-00032 TABLE F-1 Example # HEP (IC.sub.50) MOLT4
(EC.sub.50) D.1.1 +++ +++ D.1.2 ++ ++ D.1.3 +++ ++ D.1.4 +++ +++
D.1.5 +++ ++ D.1.6 ++ ++ D.1.7 ++ + D.1.8 +++ ++ D.1.9 ++ D.1.10 ++
++ D.1.11 ++ >+ D.1.12 +++ ++ D.1.13 +++ + D.1.14 ++ >+ D.2
+++ +++ D.2.1 +++ ++ D.2.2 +++ >+ D.2.3 +++ +++ D.2.4 +++ +++
D.2.5 +++ ++ D.2.6 ++ + D.2.7 +++ +++ D.2.8 ++ +++ D.2.9 +++ +++
D.2.10 +++ +++ D.3.1 +++ +++ D.3.2 +++ +++ D.3.3 +++ ++ D.3.7 +++
+++ D.3.8 +++ +++ D.3.11 +++ +++ D.3.12 +++ +++ D.3.15 +++ +++
D.3.24 +++ +++ D.3.26 +++ +++ D.3.27 +++ +++ D.3.29 +++ +++ D.3.31
++ ++ D.3.32 +++ +++ D.3.34 +++ +++ D.3.36 +++ +++ D.3.37 +++ +++
D.3.38 +++ +++ D.3.39 +++ +++ D.3.43 +++ +++ D.3.49 +++ ++ D.3.50
+++ +++ D.3.54 +++ +++ D.3.55 +++ +++ D.3.57 +++ +++ D.3.58 +++ +++
D.3.59 +++ ++ D.3.62 +++ +++ D.3.64 +++ +++ D.3.66 +++ +++ D.3.67
+++ +++ D.3.68 +++ D.3.69 +++ D.3.70 +++ +++ D.3.73 +++ +++ D.3.75
+++ +++ D.3.76 +++ D.3.77 +++ D.3.78 +++ D.3.80 +++ D.3.87 +++
D.3.89 +++ D.3.91 +++ +++ D.3.92 +++ +++ D.3.93 +++ +++ D.3.94 +++
+++ D.3.96 +++ +++ D.3.97 +++ +++ D.3.102 +++ ++ D.3.103 +++ ++
D.3.104 +++ ++ D.3.105 +++ ++ D.3.115 +++ D.3.117 +++ +++ D.3.119
+++ +++ D.3.122 +++ +++ D.3.124 +++ +++ D.3.125 +++ +++ D.3.126 +++
+++ D.3.128 +++ ++ D.3.129 +++ +++ D.3.130 +++ D.3.131 +++ +++
D.3.132 +++ +++ D.3.133 +++ ++ D.3.136 +++ >+ D.3.137 ++ +
D.3.138 ++ ++ D.3.161 +++ ++ D.3.174 ++ +++ D.3.175 ++ ++ D.3.176
+++ +++ D.3.177 +++ +++ D.3.178 ++ +++ D.3.179 +++ +++ D.3.180 +++
+++ D.3.182 ++ ++ D.3.185 +++ +++ D.3.186 +++ +++ D.3.189 +++ +++
D.3.190 +++ +++ D.3.191 +++ +++ D.3.192 ++ + D.4.3 +++ +++ D.4.4
+++ +++ D.4.6 ++ +++ D.4.7 ++ +++ D.4.8 ++ +++ D.4.9 ++ +++ D.6.3
+++ +++ D.6.5 +++ +++ D.6.8 ++ +++ D.6.9 +++ +++ D.7.1 +++ + D.7.2
+++ + D.7.3 +++ + D.7.4 +++ >+ D.7.5 +++ ++ D.7.6 +++ >+
D.7.7 +++ >+ D.7.8 +++ >+ D.7.11 +++ + D.7.12 +++ >+
D.7.17 +++ ++ D.7.19 +++ + D.7.20 +++ + D.7.21 +++ + D.7.23 +++
>+ D.7.24 +++ ++ D.7.25 +++ + D.7.26 +++ + D.7.27 +++ + D.7.28
+++ >+ D.7.30 ++ >+ D.7.31 +++ >+ D.7.32 +++ + D.7.33 +++
+ D.7.35 +++ >+ D.7.36 +++ + D.7.37 +++ >+ D.7.38 +++ ++
D.7.39 +++ + D.7.41 +++ +++ D.7.60 +++ + D.7.61 +++ >+ D.8 +++
+++ D.8.4 ++ +++ D.8.5 +++ +++ D.8.6 +++ +++ D.8.18 ++ ++ D.8.19
+++ +++ D.8.20 +++ +++ D.9 +++ +++ D.12 +++ +++ D.16.6 +++ +++ D.18
+++ +++ D.19 +++ +++ D.24.3 +++ +++ D.24.4 +++ +++ D.24.6 +++ +++
D.24.8 +++ +++ D.24.9 +++ +++ D.24.10 +++ +++ D.24.11 +++ +++
D.24.12 +++ +++ D.24.14 +++ +++ D.24.15 +++ +++ D.24.16 +++ +++
E.1.1 +++ >+ E.1.2 +++ + E.1.3 +++ ++ E.1.4 +++ ++ E.1.5 +++
>+ E.1.6 ++ + E.1.7 +++ + E.1.8 +++ >+ E.1.10 +++ E.1.11 +++
++ E.1.12 +++ >+ E.1.13 +++ + E.1.14 +++ E.1.15 +++ ++ E.1.16
+++ +++ E.1.17 +++ +++ E.1.18 +++ +++ E.1.19 +++ ++ E.1.20 +++ +++
E.1.21 +++ +++ E.1.22 +++ >+ E.1.23 +++ +++ E.1.24 +++ +++
E.1.25 +++ +++ E.1.26 +++ +++ E.1.27 +++ +++ E.1.28 +++ ++ E.1.29
+++ ++ E.1.30 +++ + E.2.1 +++ +++ E.2.2 +++ ++ E.2.3 +++ + E.2.4
+++ >+ E.2.5 +++ + E.2.6 +++ ++ E.2.7 +++ + E.2.8 +++ + E.2.9
+++ ++ E.2.10 +++ >+ E.2.11 +++ >+ E.2.12 +++ +++ E.2.13 +++
+ E.2.14 +++ >+ E.2.15 +++ >+ E.2.16 +++ >+ E.2.18 +++ +
E.2.19 +++ + E.2.20 +++ + E.2.21 +++ + E.2.22 +++ ++ E.2.23 +++ ++
E.2.24 +++ >+ E.2.25 +++ + E.2.26 +++ >+ E.2.27 +++ >+
E.2.28 +++ >+ E.2.29 +++ + E.2.31 +++ >+ E.2.32 +++ >+
E.2.33 +++ + E.2.34 +++ + E.2.35 +++ >+ E.2.36 +++ >+ E.2.37
+++ >+ E.2.38 +++ + E.2.39 +++ ++ E.2.40 +++ + E.2.41 +++ >+
E.2.42 +++ >+ E.2.45 +++ +++ E.2.46 +++ ++ E.2.47 +++ >+
E.2.48 +++ ++
E.2.49 +++ >+ E.2.50 +++ >+ E.2.51 ++ >+ E.2.52 +++ +
E.2.53 ++ >+ E.2.54 +++ >+ E.2.55 +++ + E.2.56 +++ + E.2.57
+++ + E.2.58 +++ + E.2.59 +++ + E.2.60 +++ + E.2.61 +++ + E.2.62
+++ >+ E.2.64 +++ >+ E.2.65 ++ >+ E.2.66 +++ >+ E.2.67
+++ + E.2.68 +++ >+ E.2.69 +++ >+ E.2.70 +++ >+ E.2.75 +++
>+ E.2.76 +++ + E.2.77 +++ + E.2.78 +++ + E.2.79 +++ ++ E.2.80
++ + E.2.81 ++ + E.3 +++ +++ E.3.1 +++ +++ E.3.2 +++ +++ E.3.3 +++
+++ E.3.4 ++ +++ E.3.5 +++ +++ E.3.6 +++ +++ E.3.7 +++ +++ E.3.8
+++ +++ E.3.9 +++ +++ E.3.10 +++ +++ E.4 +++ +++ E.4.1 ++ ++ E.4.2
++ +++ E.4.3 +++ +++ E.5 +++ +++ E.5.1 +++ +++ E.5.2 +++ +++ E.5.3
++ ++ E.5.5 +++ +++ E.5.6 +++ +++ E.5.7 +++ +++ E.5.8 +++ +++ E.5.9
+++ +++ E.5.10 +++ +++ E.5.11 +++ +++ E.5.12 +++ +++ E.5.13 +++ +++
E.5.16 +++ +++ E.5.17 +++ ++ E.5.18 +++ +++ E.5.19 +++ +++ E.5.20
+++ +++ E.5.21 +++ +++ E.5.22 +++ +++ E.5.24 +++ ++ E.5.25 +++ +++
E.5.26 +++ ++ E.5.27 +++ +++ E.5.28 +++ +++ E.5.29 +++ +++ E.5.30
+++ ++ E.5.31 +++ +++ E.5.32 +++ +++ E.5.33 +++ ++ E.5.34 +++ +++
E.5.35 +++ +++ E.5.36 ++ ++ E.5.37 +++ +++ E.5.40 +++ +++ E.5.41 ++
+++ F.1 +++ F.2.1 ++ ++
Pharmaceutical Formulations and Dosage Forms
[0817] When employed as pharmaceuticals, the compounds of Formula
(I) can be administered in the form of pharmaceutical compositions.
These compositions can be administered by a variety of routes
including oral, rectal, transdermal, subcutaneous, intravenous,
intramuscular, and intranasal, and can be prepared in a manner well
known in the pharmaceutical art.
[0818] This invention also includes pharmaceutical compositions
which contain, as the active ingredient, one or more of the
compounds of Formula (I) above in combination with one or more
pharmaceutically acceptable carriers. In making the compositions of
the invention, the active ingredient is typically mixed with an
excipient, diluted by an excipient or enclosed within such a
carrier in the form of, for example, a capsule, sachet, paper, or
other container. When the excipient serves as a diluent, it can be
a solid, semi-solid, or liquid material, which acts as a vehicle,
carrier or medium for the active ingredient. Thus, the compositions
can be in the form of tablets, pills, powders, lozenges, sachets,
cachets, elixirs, suspensions, emulsions, solutions, syrups,
aerosols (as a solid or in a liquid medium), ointments containing,
for example, up to 10% by weight of the active compound, soft and
hard gelatin capsules, suppositories, sterile injectable solutions,
and sterile packaged powders.
[0819] In preparing a formulation, the active compound can be
milled to provide the appropriate particle size prior to combining
with the other ingredients. If the active compound is substantially
insoluble, it can be milled to a particle size of less than 200
mesh. If the active compound is substantially water soluble, the
particle size can be adjusted by milling to provide a substantially
uniform distribution in the formulation, e.g. about 40 mesh.
[0820] Some examples of suitable excipients include lactose,
dextrose, sucrose, sorbitol, mannitol, starches, gum acacia,
calcium phosphate, alginates, tragacanth, gelatin, calcium
silicate, microcrystalline cellulose, polyvinylpyrrolidone,
cellulose, water, syrup, and methyl cellulose. The formulations can
additionally include: lubricating agents such as talc, magnesium
stearate, and mineral oil; wetting agents; emulsifying and
suspending agents; preserving agents such as methyl- and
propylhydroxy-benzoates; sweetening agents; and flavoring agents.
The compositions of the invention can be formulated so as to
provide quick, sustained or delayed release of the active
ingredient after administration to the patient by employing
procedures known in the art.
[0821] The compositions can be formulated in a unit dosage form,
each dosage containing from about 5 to about 100 mg, more usually
about 10 to about 30 mg, of the active ingredient. The term "unit
dosage forms" refers to physically discrete units suitable as
unitary dosages for human subjects and other mammals, each unit
containing a predetermined quantity of active material calculated
to produce the desired therapeutic effect, in association with a
suitable pharmaceutical excipient.
[0822] The active compound can be effective over a wide dosage
range and is generally administered in a pharmaceutically effective
amount. It will be understood, however, that the amount of the
compound actually administered will usually be determined by a
physician, according to the relevant circumstances, including the
condition to be treated, the chosen route of administration, the
actual compound administered, the age, weight, and response of the
individual patient, the severity of the patient's symptoms, and the
like.
[0823] For preparing solid compositions such as tablets, the
principal active ingredient is mixed with a pharmaceutical
excipient to form a solid preformulation composition containing a
homogeneous mixture of a compound of the present invention. When
referring to these preformulation compositions as homogeneous, the
active ingredient is typically dispersed evenly throughout the
composition so that the composition can be readily subdivided into
equally effective unit dosage forms such as tablets, pills and
capsules. This solid preformulation is then subdivided into unit
dosage forms of the type described above containing from, for
example, 0.1 to about 500 mg of the active ingredient of the
present invention.
[0824] The tablets or pills of the present invention can be coated
or otherwise compounded to provide a dosage form affording the
advantage of prolonged action. For example, the tablet or pill can
comprise an inner dosage and an outer dosage component, the latter
being in the form of an envelope over the former. The two
components can be separated by an enteric layer which serves to
resist disintegration in the stomach and permit the inner component
to pass intact into the duodenum or to be delayed in release. A
variety of materials can be used for such enteric layers or
coatings, such materials including a number of polymeric acids and
mixtures of polymeric acids with such materials as shellac, cetyl
alcohol, and cellulose acetate.
[0825] The liquid forms in which the compounds and compositions of
the present invention can be incorporated for administration orally
or by injection include aqueous solutions, suitably flavored
syrups, aqueous or oil suspensions, and flavored emulsions with
edible oils such as cottonseed oil, sesame oil, coconut oil, or
peanut oil, as well as elixirs and similar pharmaceutical
vehicles.
[0826] Compositions for inhalation or insufflation include
solutions and suspensions in pharmaceutically acceptable, aqueous
or organic solvents, or mixtures thereof, and powders. The liquid
or solid compositions may contain suitable pharmaceutically
acceptable excipients as described supra. In some embodiments, the
compositions are administered by the oral or nasal respiratory
route for local or systemic effect. Compositions in can be
nebulized by use of inert gases. Nebulized solutions may be
breathed directly from the nebulizing device or the nebulizing
device can be attached to a face masks tent, or intermittent
positive pressure breathing machine. Solution, suspension, or
powder compositions can be administered orally or nasally from
devices which deliver the formulation in an appropriate manner.
[0827] The amount of compound or composition administered to a
patient will vary depending upon what is being administered, the
purpose of the administration, such as prophylaxis or therapy, the
state of the patient, the manner of administration, and the like.
In therapeutic applications, compositions can be administered to a
patient already suffering from a disease in an amount sufficient to
cure or at least partially arrest the symptoms of the disease and
its complications. An amount adequate to accomplish this is
referred to as "therapeutically effective amount." Effective doses
will depend on the disease condition being treated as well as by
the judgement of the attending clinician depending upon factors
such as the severity of the disease, the age, weight and general
condition of the patient, and the like.
[0828] The compositions administered to a patient can be in the
form of pharmaceutical compositions described above. These
compositions can be sterilized by conventional sterilization
techniques, or may be sterile filtered. Aqueous solutions can be
packaged for use as is, or lyophilized, the lyophilized preparation
being combined with a sterile aqueous carrier prior to
administration. The pH of the compound preparations typically will
be between 3 and 11, more preferably from 5 to 9 and most
preferably from 7 to 8. It will be understood that use of certain
of the foregoing excipients, carriers, or stabilizers will result
in the formation of pharmaceutical salts.
[0829] The therapeutic dosage of the compounds of the present
invention can vary according to, for example, the particular use
for which the treatment is made, the manner of administration of
the compound, the health and condition of the patient, and the
judgment of the prescribing physician. The proportion or
concentration of a compound of the invention in a pharmaceutical
composition can vary depending upon a number of factors including
dosage, chemical characteristics (e.g., hydrophobicity), and the
route of administration. For example, the compounds of the
invention can be provided in an aqueous physiological buffer
solution containing about 0.1 to about 10% w/v of the compound for
parenteral administration. Some typical dose ranges are from about
1 .mu.g/kg to about 1 g/kg of body weight per day. In some
embodiments, the dose range is from about 0.01 mg/kg to about 100
mg/kg of body weight per day. The dosage is likely to depend on
such variables as the type and extent of progression of the disease
or disorder, the overall health status of the particular patient,
the relative biological efficacy of the compound selected,
formulation of the excipient, and its route of administration.
Effective doses can be extrapolated from dose-response curves
derived from in vitro or animal model test systems.
[0830] The present invention also includes pharmaceutical kits
useful, for example, in the treatment or prevention of inflammatory
diseases, which comprise one or more containers containing a
pharmaceutical composition comprising a therapeutically effective
amount of a compound of Formula (I). Such kits can further include,
if desired, one or more of various conventional pharmaceutical kit
components, such as, for example, containers with one or more
pharmaceutically acceptable carriers, additional containers, etc.,
as will be readily apparent to those skilled in the art.
Instructions, either as inserts or as labels, indicating quantities
of the components to be administered, guidelines for
administration, and/or guidelines for mixing the components, can
also be included in the kit.
[0831] Various modifications of the invention, in addition to those
described herein, will be apparent to those skilled in the art from
the foregoing description. Such modifications are also intended to
fall within the scope of the appended claims. Each reference cited
in the present application, including patents, published patent
applications, and journal articles, is incorporated herein by
reference in its entirety.
* * * * *